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WO2013161871A1 - Dérivé de thiophène ayant une activité inhibitrice de tlr - Google Patents

Dérivé de thiophène ayant une activité inhibitrice de tlr Download PDF

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WO2013161871A1
WO2013161871A1 PCT/JP2013/062049 JP2013062049W WO2013161871A1 WO 2013161871 A1 WO2013161871 A1 WO 2013161871A1 JP 2013062049 W JP2013062049 W JP 2013062049W WO 2013161871 A1 WO2013161871 A1 WO 2013161871A1
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alkyl group
ring
phenyl
thiophen
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Japanese (ja)
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俊司 竹村
達明 西山
裕一朗 天竺桂
正毅 山火
章泰 纐纈
宙久 徳田
祥元 三宅
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興和株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention has a Toll-like receptor (TLR) inhibitory action, and diseases caused by inhibition of signals downstream of TLR, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) ), Multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, vasculitis and other autoimmune diseases, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) Or a novel compound useful as an agent for preventing and / or treating cardiomyopathy caused by sepsis.
  • TLR Toll-like receptor
  • Non-patent Document 1 a myriad of receptors having different antigen specificities are expressed on the surface of T cells and B cells by a method called gene rearrangement, and deal with any unknown foreign antigen.
  • Non-patent Document 2 nucleic acid recognition receptors that transmit signals into cells typified by TLR not only play a role in catching infection at the front line, but also transmit signals to cells and turn on the activation of the innate immune system. There is an important role to do.
  • Non-patent Document 2 In that sense, induction of gene expression of cytokines and chemokines such as type I interferon and the group of molecules involved in antigen presentation induced by activation of the innate immune system known so far, and subsequent activity of the adaptive immune system It has become clear that the pathway leads to activation of specific immune responses by coordinating with the development (Non-patent Document 2).
  • TLR3 recognizes virus-derived double-stranded RNA
  • TLR7 similarly recognizes virus-derived single-stranded RNA
  • TLR9 recognizes bacterial CpG (cytosine guanine) DNA and is activated. CpG DNA repeats at a certain frequency with a characteristic sequence of bacterial genomic DNA that is not methylated. In mammalian genomic DNA, the frequency of CpG sequences is low and methylated frequently, so there is no immunostimulatory effect (Non-patent Document 3).
  • TLRs 7 and 9 function as receptors that recognize extracellular RNA and DNA in endosomes and lysosomes, and induce gene expression of type I interferons and inflammatory cytokines. Both are mediated by a MyD88-dependent signal transduction pathway, whereas the former involves IRAK1 / IKK ⁇ -IRF-7, while the latter involves NF- ⁇ B, IRF-5 and MAP kinase pathways.
  • MyD88 is known to associate with IRF-1 and IRF-4 in addition to IRF-7 and IRF-5 (Non-Patent Documents 4, 5, and 6), but IRF transcription factors involved downstream of TLR9 The type and role vary depending on the cell type.
  • TLR recognizes RNA or DNA as a ligand, but under normal conditions, self-nucleic acid is not recognized as a ligand and does not activate innate immunity. This is because the self-nucleic acid released by cell death is degraded before being recognized by the TLR by a nuclease in the serum.
  • the intracellular localization of TLR3, 7 and 9 not in the cell surface but in the endosome is also considered as a mechanism that does not recognize self-nucleic acids.
  • autoimmune reaction or inflammation it is considered that such a defense mechanism breaks down, forms a complex with an endogenous protein, and activates a TLR signal (Non-patent Document 7). .
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • SS Sjogren's syndrome
  • MS multiple sclerosis
  • IBD inflammatory bowel disease
  • psoriatic arthritis It is considered possible to improve cardiomyopathy due to Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis. As shown below, these several diseases have a specific relationship with TLR.
  • Non-patent Document 8 rheumatoid arthritis
  • SLE Systemic lupus erythematosus
  • Non-Patent Document 10 Systemic lupus erythematosus
  • Non-patent Document 11 results have been reported.
  • CPG 52364 Patent Document 1
  • TLR7 knockout mice MRL / lpr mice that spontaneously develop SLE-like symptoms
  • SLE-like symptoms such as a decrease in protein in urine and a decrease in blood IgG
  • Non-patent Document 11 suppression of SLE-like symptoms has also been reported by administering an inhibitory nucleic acid. From these reports, it is inferred that TLR7 is also very useful as a target of SLE.
  • EAE model which is a model of MS in mice
  • TLR2 and TLR9 knockout mice have a weak pathological condition, and the involvement of TLR has been shown (Non-Patent Document 14).
  • Non-patent Document 15 salivary gland epithelial cells of patients with Sjogren's syndrome (SS) are highly sensitive to apoptosis due to activation of TLR3, and TLR is considered to be involved.
  • TLR inhibition acts on a diseased body
  • TLR activation Have been reported to act in a suppressive manner on the pathology, and it is generally not thought that only the inhibitory action functions to recover the pathological condition, but involvement with TLR has been shown (Non-patent Document 16).
  • Non-patent Document 17 There has been a report that the contractility of cardiomyocytes has been lost by inflammatory cytokines produced by the ligand CpG-B DNA, and its action was attenuated in TLR9 knockout mice. It is thought that it is concerned with the cardiomyopathy resulting from sepsis from such a thing.
  • Hydroxychloroquine is known to have a TLR9 inhibitory action and is already used in clinical practice, but it is not so strong as a TLR9 inhibitory action, and a drug having a stronger TLR9 inhibitory action has a stronger drug effect. I can expect. Hydroxychloroquine has concerns about side effects such as chloroquine retinopathy, but it is also possible that compounds with different skeletons can eliminate such side effects.
  • low-molecular-weight drugs that exhibit strong TLR inhibitory action and can be administered orally are future rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS), inflammation
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • SS Sjogren's syndrome
  • MS multiple sclerosis
  • inflammation In the treatment of cardiomyopathy caused by inflammatory bowel disease (IBD), autoimmune diseases such as psoriatic arthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis It is considered useful.
  • IBD inflammatory bowel disease
  • Behcet's syndrome vasculitis
  • inflammation allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis It is considered useful.
  • Patent Document 2 effects as a therapeutic agent for central nervous system diseases
  • Patent Documents 3, 4, and 5 effects as a therapeutic agent for cancer therapeutic agent
  • Patent Documents 3, 4, and 5 effects as a therapeutic agent for central nervous system diseases
  • Patent Documents 3, 4, and 5 effects as a therapeutic agent for central nervous system diseases
  • Patent Documents 3, 4, and 5 effects as a therapeutic agent for central nervous system diseases
  • Patent Documents 3, 4, and 5 effects as a therapeutic agent for central nervous system diseases
  • Patent Document 7 prostaglandin E synthase inhibitor
  • Patent Document 8 calcium channel modulator
  • Non-Patent Document 18 Non-Patent Document 18
  • immunity An effect as a therapeutic agent for immune allergic diseases such as an inhibitor of cell activation (Patent Document 9) is also known.
  • any of these documents there is no description or suggestion related to the TLR inhibitory action.
  • An object of the present invention is to provide a novel compound having a low molecular TLR inhibitory action. More specifically, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, vasculitis, etc. It is to provide a medicament useful for the prevention and / or treatment of cardiomyopathy caused by autoimmune disease, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • SS Sjogren's syndrome
  • MS multiple sclerosis
  • IBD inflammatory bowel disease
  • Behcet's syndrome vasculitis
  • the present inventors have found that the thiophene derivative represented by the following general formula (1) expresses human TLR3 internally.
  • Test using ECV304 derived from human vascular endothelial cells test using HEK293 cells derived from human fetal kidney cells expressing human TLR7, HEK293 cells derived from human fetal kidney cells expressing human TLR9 And found that it has a TLR inhibitory action, and has completed the present invention.
  • Ring A represents a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring
  • Ring B represents a saturated or unsaturated aliphatic carbocyclic ring, an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring
  • ring A and ring B are each a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1-3 alkyloxy C 1-6 alkyl group, a cyano group, or a carboxy C 1.
  • Q 2 represents a single bond or a C 1-6 alkylene group, wherein the C 1-6 alkylene group is a halogen atom, an oxo group, a hydroxyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group 1 to 2 substituents selected from a C 1-3 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 alkyl group, R 4 represents a single bond, an oxygen atom or an NH group, wherein the
  • Ring C represents a saturated or unsaturated nitrogen-containing aliphatic heterocycle or nitrogen-containing aromatic heterocycle, wherein the ring C is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, or a C 1-6 alkyl Oxy group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group A substituent selected from a C 1-3 alkylcarbamoyl C 1-5 alkyl group, a C 1-6 alkylamino group, a diC 1-6 alkylamino group, and a diC 1-6 alkylamino C 1-6 alkyl group, You may have 1 to 3 Q 3 represents a single bond, a C 1-6 alkylene group or a C 2-6 alkenylene group, wherein the
  • Benzyloxycarbonyl C 1-5 alkyl group carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di-C 1- A 6 alkylamino group, a di-C 1-6 alkylamino C 1-6 alkyl group, and a group of formula (4):
  • R 5 represents a single bond, an oxygen atom or an NH group, wherein the NH group is a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-3 alkyloxy C 1-6 alkyl group, may have a C 1-3 alkylsulfonyl group, and C 6-10 aryl C 1-3 substituent selected from alkyl groups
  • Ring D represents a saturated or unsaturated aliphatic
  • X represents the formula (3) and the ring C represents a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring
  • the ring Y represents a saturated or unsaturated fat having a substituent represented by the formula (4).
  • An aromatic carbocyclic ring an aromatic carbocyclic ring, a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring
  • ring Y has a substituent represented by formula (4) and ring D represents an aromatic carbocycle
  • ring Y is a saturated or unsaturated aliphatic carbocyclic ring, saturated or unsaturated nitrogen-containing An aliphatic heterocycle or a nitrogen-containing aromatic heterocycle
  • X represents the formula (3) and Q 3 represents an alkylene group having an oxo group
  • the ring Y is a saturated or unsaturated aliphatic carbocyclic ring, or a saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring.
  • the ring Y is a halogen atom, C 1-6 alkyl group, hydroxyl group, C 1-6 alkyloxy group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1- 5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di May have 1 to 3 substituents selected from a C 1-6 alkylamino group, a diC 1-6 alkylamino C 1-6 alkyl group, and a group of formula (4);
  • Q 1 represents a single bond, a C 1-6 alkylene group or a C 2-6 alkenylene group, wherein the C 1-6 alkylene group or C 2-6 alkenylene group is a halogen atom, an oxo group,
  • X represents formula (2),
  • ring B represents an aromatic carbocycle, a saturated aliphatic carbocycle, or a nitrogen-containing aromatic heterocycle, wherein the ring B is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, C 1- 6 alkyloxy group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 Substitution selected from alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di-C 1-6 alkylamino group and di-C 1-6 alkylamino C 1-6 alkyl group May have 1 to 3 groups, The compound according to the above [1], or a salt thereof, or a solvate thereof.
  • X represents formula (2),
  • ring A represents a pyrrolidine ring, a piperidine ring, a piperazine ring or a tetrahydropyridine ring
  • Ring B is a benzene ring, cyclohexane ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, oxadiazole ring or Showing the thiadiazole ring
  • ring A and ring B are each a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1-3 alkyloxy C 1-6 alkyl group, a cyano group, or a carboxy C
  • X represents formula (3),
  • ring C represents a saturated nitrogen-containing aliphatic heterocycle or a nitrogen-containing aromatic heterocycle, wherein the ring C is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy Group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, A substituent selected from a C 1-3 alkylcarbamoyl C 1-5 alkyl group, a C 1-6 alkylamino group, a diC 1-6 alkylamino group and a diC 1-6 alkylamino C 1-6 alkyl group; You may have up to 3 Q 3 represents a single bond or a C 2-6 alkenylene group, wherein the C 2-6 alkenylene group
  • Q 1 represents a single bond or a C 1-6 alkylene group, wherein the C 1-6 alkylene group is a halogen atom, an oxo group, a hydroxyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, C 1-3 alkyloxy C 1-6 alkyl group and a C 6-10 aryl C 1-3 substituent selected from alkyl groups may have 1 to 2,
  • Ring Y represents an aromatic carbocyclic ring, a saturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring, wherein said ring Y is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, C 1- 6 alkyloxy group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 An alkyl group, a C 1-3 alkylcarbamoyl C 1-5 alkyl group, a C 1-6 alkylamino group, a diC 1-6 alkylamino group, a diC 1-6 alkylamino C 1-6 alkyl group, and a formula ( 1 to 3 substituents selected from the group 4) may be included.
  • Ring Y is a benzene ring, piperidine ring, pyrrolidine ring, piperazine ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring Represents an oxadiazole ring or a thiadiazole ring, wherein the ring Y is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1-3 alkyloxy C 1-6 alkyl group Cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group,
  • Ring Y has a substituent represented by formula (4),
  • ring D represents a saturated aliphatic carbocyclic ring, aromatic carbocyclic ring or saturated nitrogen-containing aliphatic heterocyclic ring, wherein the ring D is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, C 1-6 alkyloxy group, C 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1 -5 alkyl group, C 1-3 alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di-C 1-6 alkylamino group and di-C 1-6 alkylamino C 1-6 alkyl group May have 1 to 3 substituents
  • Q 4 represents a single bond or a C 1-6 alkylene
  • the ring D represents a cyclohexane ring, a benzene ring, a pyrrolidine ring, a piperidine ring or a piperazine ring, wherein the ring D is a halogen atom, a C 1-6 alkyl group, a hydroxyl group, a C 1-6 alkyloxy group, a C 1 1-3 alkyloxy C 1-6 alkyl group, cyano group, carboxy C 1-5 alkyl group, benzyloxycarbonyl C 1-5 alkyl group, carbamoyl group, amide group, carbamoyl C 1-5 alkyl group, C 1- 1 to 3 substituents selected from 3- alkylcarbamoyl C 1-5 alkyl group, C 1-6 alkylamino group, di-C 1-6 alkylamino group and di-C 1-6 alkylamino C 1-6 alkyl group May have, The compound according to [8] above, or a salt thereof,
  • the compound represented by the general formula (1) is N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 1) , 2-[(1-benzylpiperidin-4-yl) amino] -N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ acetamide (Example 2), N- ⁇ 3-[(1-benzylpiperidin-4-yl) amino] propyl ⁇ -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 3), 5- [4- (4-Methylpiperazin-1-yl) phenyl] -N- ⁇ 3-[(1-methylpiperidin-4-yl) amino] prop
  • autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, multiple sclerosis, inflammatory bowel disease, psoriatic arthritis, Behcet's syndrome or vasculitis .
  • the present invention is selected from the group consisting of TLR3, TLR7 and TLR9 containing the compound according to any one of [1] to [11] above, or a salt thereof, or a solvate thereof as an active ingredient.
  • the present invention relates to a preventive and / or therapeutic agent for diseases caused by activation of at least one signal. More specifically, the present invention relates to rheumatoid arthritis (RA), systemic, comprising the compound according to any one of the above [1] to [11], or a salt thereof, or a solvate thereof as an active ingredient.
  • RA rheumatoid arthritis
  • the present invention relates to a preventive and / or therapeutic agent for cardiomyopathy due to rejection, graft-versus-host disease (GvHD) or sepsis.
  • the present invention also relates to a disease caused by activation of at least one signal selected from the group consisting of TLR3, TLR7 and TLR9, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) , Multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) Or the use of the compound according to any one of the above [1] to [11], or a salt thereof, or a solvate thereof for the manufacture of an agent for preventing and / or treating cardiomyopathy due to sepsis, etc. .
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • SS Sjogren's syndrome
  • MS Multiple sclerosis
  • the present invention provides a TLR3 characterized by administering an effective amount of the compound according to any one of the above [1] to [11], or a salt thereof, or a solvate thereof, Diseases resulting from activation of at least one signal selected from the group consisting of TLR7 and TLR9, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), multiple sclerosis (MS) Prevention of autoimmune diseases such as inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis cardiomyopathy And / or a therapeutic method.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • SS Sjogren's syndrome
  • MS multiple sclerosis
  • IBD inflammatory bowel disease
  • the present invention also relates to the compound according to any one of [1] to [11] above, or a salt thereof, or a solvate thereof for use as a medicament.
  • the present invention also relates to a disease caused by activation of at least one signal selected from the group consisting of TLR3, TLR7 and TLR9, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) , Multiple sclerosis (MS), inflammatory bowel disease (IBD), psoriatic arthritis, Behcet's syndrome, autoimmune diseases such as vasculitis, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD)
  • the present invention relates to the compound according to any one of [1] to [11] above, or a salt thereof, or a solvate thereof for use in prevention and / or treatment of cardiomyopathy due to sepsis.
  • the compound represented by the general formula (1) or a salt thereof, or a solvate thereof, which is an active ingredient of at least one inhibitor selected from the group consisting of TLR3, TLR7 and TLR9 of the present invention is RA, Useful for the prevention and / or treatment of autoimmune diseases such as SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis cardiomyopathy .
  • autoimmune diseases such as SLE, SS, MS, IBD, psoriatic arthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection, GvHD or sepsis cardiomyopathy .
  • saturated aliphatic carbocycle refers to a 4- to 7-membered aliphatic carbocycle having no multiple bond between adjacent ring carbon atoms.
  • saturated aliphatic carbocycle examples include cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane and the like.
  • “unsaturated aliphatic carbocycle” refers to a 4- to 7-membered aliphatic carbocycle having one or more multiple bonds between adjacent ring member atoms.
  • Examples of the “unsaturated aliphatic carbocycle” include, for example, cyclobutene ring, cyclopentene ring, cyclohexene ring, 1,3-cyclohexadiene ring, 1,4-cyclohexadiene ring, 1,3-cycloheptadiene ring, 1, Examples include 4-cycloheptadiene ring.
  • saturated nitrogen-containing aliphatic heterocycle means that there are no multiple bonds between adjacent ring member atoms, one or more nitrogen atoms as ring member atoms, and the rest Represents a 4- to 7-membered aliphatic heterocyclic ring in which the ring member atom is a carbon atom, nitrogen atom, oxygen atom, or sulfur atom.
  • saturated nitrogen-containing aliphatic heterocycle include azetidine ring, pyrrolidine ring, piperidine ring, azepane ring, piperazine ring and the like.
  • an “unsaturated nitrogen-containing aliphatic heterocycle” has one or more multiple bonds between adjacent ring member atoms, and contains one or more nitrogen atoms as ring member atoms. And a 4- to 7-membered aliphatic heterocyclic ring in which the remaining ring member atoms are carbon atoms, nitrogen atoms, oxygen atoms, or sulfur atoms.
  • Examples of the “unsaturated nitrogen-containing aliphatic heterocycle” include azetine ring, pyrroline ring, tetrahydropyridine ring, dihydropyridine ring, tetrahydropyrazine ring, dihydropyrazine ring, tetrahydroazepine ring, oxazine ring and thiazine ring. .
  • aromatic carbocycle means a 6 to 10 membered aromatic carbocycle in which all ring member atoms are carbon atoms.
  • aromatic carbocycle examples include a benzene ring, an azulene ring, a naphthalene ring and the like.
  • nitrogen-containing aromatic heterocycle means one or more nitrogen atoms as ring member atoms, and the remaining ring members are hetero atoms other than nitrogen atoms (oxygen or sulfur atoms). Or a 5- to 9-membered aromatic heterocycle which is a carbon atom.
  • nitrogen-containing aromatic heterocycle examples include pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, oxadi An azole ring, a thiadiazole ring, an indole ring, etc. are mentioned.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • C 1-6 alkyl group means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
  • Examples of the “C 1-6 alkyl group” include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-methylbutyl group, Examples include 2,2-dimethylpropyl group and n-hexyl group.
  • C 1-6 alkyloxy group means a group in which a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms is bonded to an oxygen atom.
  • Examples of the “C 1-6 alkyloxy group” include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, 2- Examples include methylbutoxy group, 2,2-dimethylpropoxy group, n-hexyloxy group and the like.
  • “carboxy C 1-5 alkyl group” means a straight-chain saturated hydrocarbon group having 1 to 5 carbon atoms substituted with a carboxy group at the end.
  • Examples of the “carboxy C 1-5 alkyl group” include carboxymethyl group, carboxyethyl group, carboxypropyl group, carboxybutyl group, carboxypentyl group and the like.
  • benzyloxycarbonyl C 1-5 alkyl group means a straight-chain saturated hydrocarbon group having 1 to 5 carbon atoms substituted with a benzyloxycarbonyl group.
  • examples of the “benzyloxycarbonyl C 1-5 alkyl group” include benzyloxycarbonylmethyl group, benzyloxycarbonylethyl group, benzyloxycarbonylpropyl group, benzyloxycarbonylbutyl group, benzyloxycarbonylpentyl group and the like.
  • “carbamoyl C 1-5 alkyl group” means a straight-chain saturated hydrocarbon group having 1 to 5 carbon atoms substituted with a carbamoyl group at the terminal.
  • Examples of the “carbamoyl C 1-5 alkyl group” include carbamoylmethyl group, carbamoylethyl group, carbamoylpropyl group, carbamoylbutyl group, carbamoylpentyl group and the like.
  • the “C 1-3 alkylcarbamoyl C 1-5 alkyl group” means the carbamoyl C 1-5 alkyl group substituted at the end with a C 1-3 alkyl group.
  • Examples of the “C 1-3 alkylcarbamoyl C 1-5 alkyl group” include, for example, a 1-methylamino-1-oxoethane-2-yl group, a 1-methylamino-1-oxopropan-3-yl group, Methylamino-1-oxobutan-4-yl group, 1-methylamino-1-oxopentan-5-yl group, 1-methylamino-1-oxohexane-6-yl group, 1-ethylamino-1-oxoethane -2-yl group, 1-ethylamino-1-oxopropan-3-yl group, 1-ethylamino-1-oxobutan-4-yl group, 1-ethylamino
  • C 1-6 alkylamino group means an amino group in which a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms is substituted.
  • Examples of the “C 1-6 alkylamino group” include, for example, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, tert-butylamino group, n- Examples include pentylamino group, 2-methylbutylamino group, 2,2-dimethylpropylamino group, n-hexylamino group and the like.
  • the “di-C 1-6 alkylamino group” is an amino group in which a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms is the same or different and is disubstituted. means.
  • Examples of the “di-C 1-6 alkylamino group” include (ethyl) (methyl) amino group, (isopropyl) (n-propyl) amino group, (n-butyl) (isobutyl) amino group, (tert-butyl) ) (N-pentyl) amino group, (2,2-dimethylpropyl) (2-methylbutyl) amino group, dimethylamino group, diethylamino group, di-n-propylamino group, di-isopropylamino group, di-n- Examples thereof include a butylamino group, a di-tert-butylamino group, a di-n-pentylamino group, and a di-n-he
  • di-C 1-6 alkylamino C 1-6 alkyl group C 1-6 group that the di-C 1-6 alkylamino group at the end of the alkyl group is substituted Means.
  • examples of the “di-C 1-6 alkylamino C 1-6 alkyl group” include (ethyl) (methyl) aminomethyl group, (isopropyl) (n-propyl) aminomethyl group, (n-butyl) (isobutyl) Aminomethyl group, (tert-butyl) (n-pentyl) aminomethyl group, (2,2-dimethylpropyl) (2-methylbutyl) aminomethyl group, dimethylaminomethyl group, diethylaminomethyl group, di-n-propylamino Methyl group, di-isopropylaminomethyl group, di-n-butylaminomethyl group, di-t-butylaminomethyl group, di-n-pentylaminomethyl group
  • C 1-6 alkylene group means a saturated divalent straight chain or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms.
  • Examples of the “C 1-6 alkylene group” include methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, isobutylene group, tert-butylene group, n-pentylene group, 2-methylbutylene. Group, 2,2-dimethylpropylene group, n-hexylene group and the like.
  • C 2-6 alkenylene group means a divalent linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms containing one double bond.
  • Examples of the “C 2-6 alkenylene group” include vinylene group, propenylene group, 1-butenylene group, 2-butenylene group, 1-pentenylene group, 2-pentenylene group, 1-hexenylene group, 2-hexenylene group, 3 -A hexenylene group and the like.
  • hydroxy C 1-6 alkyl group means a linear or branched C 1-6 alkyl group having a terminal substituted with a hydroxyl group.
  • Examples of the “hydroxy C 1-6 alkyl group” include, for example, hydroxymethyl group, hydroxyethyl group, hydroxy-n-propyl group, hydroxyisopropyl group, hydroxy-n-butyl group, hydroxyisobutyl group, hydroxy-tert-butyl group Hydroxy-n-pentyl group, hydroxy-2-methylbutyl group, hydroxy-2,2-dimethylpropyl group, hydroxy-n-hexyl group and the like.
  • C 1-3 alkyloxy C 1-6 alkyl group means a hydroxy group of a hydroxy C 1-6 alkyl group substituted with a linear or branched C 1-3 alkyl group. Means the group.
  • Examples of the “C 1-3 alkyloxy C 1-6 alkyl group” include methoxymethyl group, methoxyethyl group, methoxy-n-propyl group, methoxyisopropyl group, methoxy-n-butyl group, methoxyisobutyl group, methoxy -Tert-butyl group, methoxy-n-pentyl group, methoxy-2-methylbutyl group, methoxy-2,2-dimethylpropyl group, methoxy-n-hexyl group, ethoxymethyl group, ethoxyethyl group, ethoxy-n-propyl Group, ethoxyisopropyl group, ethoxy-n-butyl group,
  • C 1-3 alkylsulfonyl group means a sulfonyl group substituted with a linear or branched C 1-3 alkyl group.
  • Examples of the “C 1-3 alkylsulfonyl group” include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group and the like.
  • C 6-10 aryl C 1-3 alkyl group means a straight or branched C 1-3 alkyl group substituted with a 6-10 membered aromatic carbocycle. To do.
  • Examples of the “C 6-10 aryl C 1-3 alkyl group” include benzyl group, phenethyl group, 1-phenyl-n-propan-1-yl group, 2-phenyl-n-propan-1-yl group, 3-phenyl-n-propan-1-yl group, 1-phenyl-isopropan-2-yl group, 2-phenyl-isopropan-2-yl group, azulenemethyl group, 1-azulenethan-1-yl group 2-azulenethan-1-yl group, 1-azulene-n-propan-1-yl group, 2-azulene-n-propan-1-yl group, 3-azulene-n-propan-1-yl group, 1-azulene-isopropan-2-yl group, 2-azulene-is
  • the saturated nitrogen-containing aliphatic heterocyclic ring is preferably a piperidine ring, a piperazine ring, or a pyrrolidine ring.
  • the unsaturated nitrogen-containing aliphatic heterocyclic ring is preferably a 1,2,3,6-tetrahydropyridine ring.
  • the aromatic carbocycle is preferably a benzene ring.
  • the nitrogen-containing aromatic heterocycle is preferably a pyridine ring, an indole ring or a pyrazole ring.
  • the halogen atom is preferably a bromine atom.
  • the C 1-6 alkyl group is preferably a methyl group, an isopropyl group or an isobutyl group.
  • the C 1-6 alkyloxy group is preferably a methoxy group.
  • the carboxy C 1-5 alkyl group is preferably a carboxybutyl group.
  • the benzyloxycarbonyl C 1-5 alkyl group is preferably a benzyloxycarbonylmethyl group or a benzyloxycarbonylpentyl group.
  • the carbamoyl C 1-5 alkyl group is preferably a carbamoylpentyl group.
  • the C 1-3 alkylcarbamoyl C 1-5 alkyl group is preferably a 1-methylamino-1-oxohexane-6-yl group.
  • the C 1-6 alkylamino group is preferably a methylamino group.
  • the diC 1-6 alkylamino group is preferably a dimethylamino group.
  • the C 1-6 alkylene group is preferably a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group.
  • the hydroxy C 1-6 alkyl group is preferably a hydroxy-n-propyl group or a hydroxy-n-pentyl group.
  • the C 1-3 alkyloxy C 1-6 alkyl group is preferably a methoxyethyl group.
  • the C 1-3 alkylsulfonyl group is preferably a methylsulfonyl group.
  • the C 6-10 aryl C 1-3 alkyl group is preferably a benzyl group.
  • ring A is preferably a pyrrolidine ring, piperidine ring, piperazine ring or tetrahydropyridine ring, more preferably a piperidine ring, piperazine ring or tetrahydropyridine ring.
  • examples of the substituent that the ring A may have include a C 1-6 alkyl group, a C 1-3 alkylcarbamoyl C 1-5 alkyl group, and a benzyloxycarbonyl C 1-5 alkyl group.
  • a methyl group, an isopropyl group, a 1-methylamino-1-oxopentan-5-yl group, a benzyloxycarbonylmethyl group, and a benzyloxycarbonylpentyl group are more preferable.
  • ring B is preferably an aromatic carbocyclic ring, a saturated aliphatic carbocyclic ring, or a nitrogen-containing aromatic heterocyclic ring.
  • Triazine ring, pyrrole ring, pyrazole ring, isoxazole ring, oxazole ring, isothiazole ring, thiazole ring, oxadiazole ring, thiadiazole ring are more preferable, benzene ring, cyclohexane ring, pyridine ring, pyrazole ring are more preferable. .
  • the substituent that ring B may have is preferably a hydroxyl group, a C 1-6 alkyloxy group, a cyano group, or a carbamoyl group.
  • the C 1-6 alkyloxy group is more preferably a methoxy group.
  • Q 2 is preferably a single bond or a C 1-6 alkylene group, more preferably a single bond, a methylene group, an ethylene group, an n-propylene group, an n-butylene group or an n-pentylene group. .
  • the substituent that Q 2 may have is preferably an oxo group.
  • the substitution position of R 4 to the ring B is not particularly limited as long as substitution is possible.
  • the ring B is a 6-membered ring
  • the ring B of the thiophene ring as the mother nucleus
  • it is the 3rd or 4th position counted from the bonding position of, for example, when the ring B is a 5-membered ring, it is preferably the 3rd position counted from the bonding position to the ring B of the thiophene ring which is the mother nucleus. preferable.
  • ring C is preferably a saturated nitrogen-containing aliphatic heterocycle or nitrogen-containing aromatic heterocycle, and a piperidine ring, pyrrolidine ring, piperazine ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring , A triazine ring, a pyrrole ring, a pyrazole ring, an isoxazole ring, an oxazole ring, an isothiazole ring, a thiazole ring, an oxadiazole ring, a thiadiazole ring, and an indole ring, more preferably a piperazine ring and an indole ring.
  • the substituent that the ring C may have is preferably a C 1-6 alkyl group and a diC 1-6 alkylamino C 1-6 alkyl group, a methyl group, a dimethylaminopropyl group Is more preferable.
  • Q 3 is preferably a single bond or a C 2-6 alkenylene group, and the C 2-6 alkenylene group is more preferably a propenylene group.
  • the substituent that Q 3 may have is preferably an oxo group.
  • ring Y is preferably an aromatic carbocyclic ring, a saturated nitrogen-containing aliphatic heterocyclic ring, or a nitrogen-containing aromatic heterocyclic ring.
  • examples of the substituent that the ring Y may have include a C 1-6 alkyl group, a diC 1-6 alkylamino group, a diC 1-6 alkylamino C 1-6 alkyl group, And groups of formula (4) are preferred, methyl groups, dimethylamino groups, dimethylaminomethyl groups and groups of formula (4) are more preferred.
  • the substitution position is not particularly limited as long as substitution is possible.
  • R 1 is bonded to ring Y.
  • at least one is substituted at the 4-position counting from 1, for example, when the ring Y is a 5-membered ring, at least one is substituted at the 2-position counting from the bonding position of R 1 to the ring Y. preferable.
  • ring D is preferably an aromatic carbocyclic ring, a saturated aliphatic carbocyclic ring, or a saturated nitrogen-containing aliphatic heterocyclic ring, and a benzene ring, a cyclohexane ring, a pyrrolidine ring, a piperazine ring, or a piperidine ring. More preferred are benzene, cyclohexane, piperazine and piperidine rings.
  • examples of the substituent that the ring D may have include a C 1-6 alkyl group, a diC 1-6 alkylamino group, and a diC 1-6 alkylamino C 1-6 alkyl group.
  • a methyl group, a dimethylamino group, and a dimethylaminomethyl group are more preferable.
  • Q 4 is preferably a single bond or a C 1-6 alkylene group, more preferably a single bond or a methylene group.
  • R 5 is preferably a single bond or an NH group.
  • Q 1 is preferably a single bond or a C 1-6 alkylene group, more preferably a single bond, a methylene group, an ethylene group, an n-propylene group, an n-butylene group or an n-pentylene group.
  • the substituent of Q 1 is preferably a C 1-6 alkyl group, a C 1-3 alkyloxy C 1-6 alkyl group, or a C 6-10 aryl C 1-3 alkyl group, An isobutyl group, a methoxyethyl group, and a benzyl group are more preferable.
  • R 1 when R 1 is an NH group and is substituted, the substituent is preferably a hydroxy C 1-6 alkyl group or a C 1-3 alkylsulfonyl group, and a hydroxy-n-propyl group More preferred are a hydroxy-n-pentyl group and a methylsulfonyl group.
  • N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 1) , 2-[(1-benzylpiperidin-4-yl) amino] -N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ acetamide (Example 2), N- ⁇ 3-[(1-benzylpiperidin-4-yl) amino] propyl ⁇ -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide (Example 3), 5- [4- (4-Methylpiperazin-1-yl) phenyl] -N- ⁇ 3-[(1-methylpiperazin-1-yl) phenyl] thiophene-2-carbox
  • the thiophene derivative represented by the general formula (1) of the present invention, or a salt thereof, or a solvate thereof includes not only the thiophene derivative of the present invention, but also a pharmaceutically acceptable salt thereof, various hydrations thereof. Substances, solvates, substances having crystalline polymorphs, and substances that become prodrugs of these substances.
  • salts acceptable as the thiophene derivative represented by the general formula (1) of the present invention include inorganic acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid). And acid addition salts with organic acids (for example, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.).
  • solvate of the thiophene derivative represented by the general formula (1) of the present invention or a pharmaceutically acceptable salt thereof examples include hydrates and various solvates (for example, solvates with alcohols such as ethanol). Etc.).
  • the thiophene derivative represented by the general formula (1) of the present invention can be produced by a known method. Although the manufacturing method of a thiophene derivative is shown in the following reaction process drawing, a manufacturing method is not limited to this.
  • the compound (I) of the present invention can be produced from the 2-nitrothiophene derivative (II).
  • R 1 , R 2 , R 3 , X, Q 1 and ring Y are the same as defined above, A 1 represents a leaving group, R 6 and R 7 represent a hydrogen atom or C 1-6 alkyl Group, R 6 and R 7 may be combined to form a ring, and R 8 represents a halogen atom.
  • Step 1 The coupling reaction between the thiophene derivative (II) having a leaving group and the borane compound (III) can produce the thiophene derivative (IV) using the Suzuki-Miyaura coupling reaction.
  • the metal catalyst, base and reaction conditions used are not particularly limited as long as they are reagents and conditions used for the Suzuki-Miyaura coupling reaction. Miyaura, A .; Suzuki, Chem. Rev. The methods described in 1995, 95, 2457-2483, (1995) and the like can be used.
  • the metal catalyst to be used is not particularly limited.
  • the base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium, and tert-butoxy potassium.
  • the solvent is not particularly limited, and examples thereof include ethers such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; aromatic hydrocarbons such as toluene; amides such as N, N-dimethylformamide and N-methylpyrrolidone. Dimethyl sulfoxide, water and the like can be used alone or in combination.
  • the reaction temperature is 0 ° C. to 200 ° C., preferably 60 ° C. to 150 ° C.
  • the reaction time is 30 minutes to 48 hours, preferably 1 hour to 20 hours.
  • the borane compound (III) used in the above reaction a commercially available one can be used as it is, or it can be suitably produced by a known method, but is not limited thereto.
  • the thiophene derivative (IV) can be produced by a coupling reaction between the thiophene derivative (II) having a leaving group and the halogen compound (III ′).
  • the solvent is not particularly limited.
  • halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; ester solvents such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; Ethers such as tetrahydrofuran and 1,4-dioxane; Nitriles such as acetonitrile and propionitrile; Amides such as N, N-dimethylformamide and N-methylpyrrolidone; Water and the like can be used alone or in combination.
  • the metal catalyst to be used is not particularly limited.
  • a ligand such as o-tritoluylphosphine, triphenylphosphine, 1,1'-bis (diphenylphosphino) ferrocene, tri-tert-butylphosphine, and the like may be added.
  • an organic base such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, and trimethylamine may be added.
  • the reaction temperature is ⁇ 20 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.
  • the reaction time is 5 minutes to 2 days, preferably 1 hour to 20 hours.
  • the aminothiophene derivative (V) can be produced by reacting the nitro group of the thiophene derivative (IV) in a solvent in the presence of a reducing agent.
  • This reduction method is (a) catalytic hydrogenation in which a nitro group is reduced using a catalytic hydrogen reduction catalyst in a hydrogen atmosphere in a suitable inert solvent, or (b) a metal in a suitable inert solvent.
  • the reduction is carried out by metal reduction using a metal salt and acid or a mixture of metal or metal salt and alkali metal hydroxide, sulfide or ammonium salt as a reducing agent to reduce the nitro group.
  • examples of the solvent include water; organic acid solvents such as acetic acid; alcohol solvents such as methanol, ethanol and isopropanol; hydrocarbon solvents such as n-hexane and cyclohexane; -Ether solvents such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether; ester solvents such as ethyl acetate and methyl acetate; aprotic polar solvents such as N, N-dimethylformamide, etc., or mixed solvents thereof can be used. .
  • organic acid solvents such as acetic acid
  • alcohol solvents such as methanol, ethanol and isopropanol
  • hydrocarbon solvents such as n-hexane and cyclohexane
  • -Ether solvents such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether
  • the catalytic hydrogen reduction catalyst for example, palladium, palladium-black, palladium-carbon, platinum-carbon, platinum, platinum oxide, copper chromite, Raney nickel and the like can be used alone or in combination.
  • the reaction temperature is ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is 30 minutes to 48 hours, preferably 1 hour to 24 hours.
  • the solvent examples include water; organic acid solvents such as acetic acid; alcohol solvents such as methanol or ethanol; ether solvents such as tetrahydrofuran and 1,4-dioxane.
  • the reaction temperature is, for example, 0 ° C. to 150 ° C., preferably 50 ° C. to 120 ° C. when zinc and acetic acid are used as the reducing agent.
  • the reaction time is 1 minute to 12 hours, preferably 1 minute to 6 hours.
  • Step 3 The dehydration condensation reaction between the aminothiophene derivative (V) and the carboxylic acid derivative (VI) uses a condensing agent in the presence or absence of a base in the solvent and in the presence or absence of a condensation accelerator. Or after the carboxylic acid is made the active intermediate.
  • the solvent is not particularly limited.
  • halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; ester solvents such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; Ethers such as tetrahydrofuran and 1,4-dioxane; Nitriles such as acetonitrile and propionitrile; Amides such as N, N-dimethylformamide and N-methylpyrrolidone; Water and the like can be used alone or in combination. .
  • the base is not particularly limited.
  • organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine, lithium hydride, sodium hydride, hydrogenated Alkali metal hydrides such as potassium, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate, An alkali metal bicarbonate such as potassium bicarbonate can be used.
  • the reaction temperature is ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.
  • the reaction between the aminothiophene derivative (V) and the acid halide derivative (VI ′) can be performed in a solvent in the presence or absence of a base.
  • the solvent is not particularly limited.
  • halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane
  • ester solvents such as ethyl acetate and isopropyl acetate
  • aromatic hydrocarbons such as toluene and benzene
  • Ethers such as tetrahydrofuran and 1,4-dioxane
  • Nitriles such as acetonitrile and propionitrile
  • Amides such as N, N-dimethylformamide and N-methylpyrrolidone; Water and the like can be used alone or in combination.
  • the base is not particularly limited.
  • organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine, lithium hydride, sodium hydride, hydrogenated Alkali metal hydrides such as potassium, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate, An alkali metal bicarbonate such as potassium bicarbonate can be used.
  • the reaction temperature is ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.
  • the compound (I) of the present invention can be produced from the thiophenecarbonyl derivative represented by the general formula (VII).
  • R 1 , R 2 , R 3 , X, Q 1 and ring Y are the same as defined above, A 1 represents a leaving group, A 2 represents OH or a leaving group, R 6 and R 7 represents a hydrogen atom or a C 1-6 alkyl group, and R 6 and R 7 may be combined to form a ring. ]
  • the thiophene derivative (I) can be produced by a combination of Step 4 and Step 5.
  • the coupling reaction between the thiophene derivative (VII) having a leaving group or a condensed derivative of the thiophene derivative (VII) and the amine derivative (VIII) and the borane compound (III) is a Suzuki-Miyaura coupling reaction.
  • the metal catalyst, base and reaction conditions to be used are not particularly limited as long as they are reagents and conditions generally used for the Suzuki-Miyaura coupling reaction. Miyaura, A.A. Suzuki, Chem. Rev. 1995, 95, 2457-2483, (1995) can be used.
  • the metal catalyst to be used is not particularly limited.
  • the base is not particularly limited, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, tert-butoxy sodium, and tert-butoxy potassium. Sodium carbonate and cesium carbonate.
  • the solvent is not particularly limited.
  • ethers such as tetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether
  • aromatic hydrocarbons such as benzene and toluene
  • N, N-dimethylformamide, N-methylpyrrolidone and the like Amides of dimethyl sulfoxide, water and the like can be used alone or in combination.
  • the reaction temperature is 0 ° C. to 200 ° C., preferably 60 ° C. to 150 ° C.
  • the reaction time is 30 minutes to 48 hours, preferably 1 hour to 20 hours.
  • the borane compound (III) used in the above reaction a commercially available one can be used as it is, or it can be appropriately produced by a known method, but is not limited thereto.
  • Step 5 The reaction of thiophene derivative (VII) or a coupling derivative of thiophene derivative (VII) with borane compound (III) and amine derivative (VIII) is carried out in the presence or absence of a base in a solvent.
  • the condensation can be carried out using a condensing agent in the presence or absence of an accelerator, or using carboxylic acid as an active intermediate.
  • the solvent is not particularly limited.
  • halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; esters such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; tetrahydrofuran Ethers such as 1,4-dioxane; nitriles such as acetonitrile and propionitrile; amides such as N, N-dimethylformamide and N-methylpyrrolidone; water and the like can be used alone or in combination.
  • the base is not particularly limited.
  • organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine, lithium hydride, sodium hydride, hydrogenated Mosquito Alkali metal hydrides such as lithium, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium hydrogen carbonate, An alkali metal bicarbonate such as potassium bicarbonate can be used.
  • the reaction temperature is generally ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C. (depending on the starting materials and reagents used).
  • the reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.
  • the compound (I) of the present invention can be produced from the 2-amino-thiophene derivative (V).
  • the thiophene derivative (I) can be produced by a urea formation reaction between the amine-containing thiophene derivative (V) and the amine derivative (VIII).
  • the solvent is not particularly limited.
  • halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; esters such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; Ethers such as tetrahydrofuran and 1,4-dioxane; Nitriles such as acetonitrile and propionitrile; Amides such as N, N-dimethylformamide and N-methylpyrrolidone; Water and the like can be used alone or in combination.
  • a base may be added as necessary, and the base is not particularly limited.
  • organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, and trimethylamine Can be used.
  • the reaction reagent for forming urea is not particularly limited, and phenyl chloroformate, 4-nitrophenyl chloroformate, carbonyldiimidazole, triphosgene and the like can be used.
  • the reaction temperature is generally ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C. (depending on the starting materials and reagents used).
  • the reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.
  • the compound (I) of the present invention can be produced from the 2-amino-thiophene derivative (V).
  • R 1 , R 2 , R 3 , X, Q 1 and ring Y are the same as defined above, A 1 represents a leaving group, and R 8 represents a halogen atom.
  • a thiophene derivative (X) having a leaving group can be produced by a dehydration condensation reaction between the aminothiophene derivative (V) and the carboxylic acid derivative (IX).
  • the dehydration condensation reaction can be carried out using a condensing agent in the presence or absence of a base in a solvent, in the presence or absence of a condensation accelerator, or after using a carboxylic acid as an active intermediate.
  • the solvent is not particularly limited.
  • halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; ester solvents such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; Ethers such as tetrahydrofuran and 1,4-dioxane; Nitriles such as acetonitrile and propionitrile; Amides such as N, N-dimethylformamide and N-methylpyrrolidone; Water and the like can be used alone or in combination. .
  • the base is not particularly limited.
  • organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine, lithium hydride, sodium hydride, hydrogenated Alkali metal hydrides such as potassium, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate, An alkali metal bicarbonate such as potassium bicarbonate can be used.
  • the reaction temperature is ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.
  • the thiophene derivative (X) having a leaving group can be produced by the reaction of the aminothiophene derivative (V) and the acid halide derivative (IX ′).
  • the reaction can be performed in a solvent in the presence or absence of a base.
  • the solvent is not particularly limited.
  • halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; ester solvents such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; Ethers such as tetrahydrofuran and 1,4-dioxane; Nitriles such as acetonitrile and propionitrile; Amides such as N, N-dimethylformamide and N-methylpyrrolidone; Water and the like can be used alone or in combination. .
  • the base is not particularly limited.
  • organic bases such as pyridine, DMAP, collidine, lutidine, DBU, DBN, DABCO, triethylamine, diisopropylethylamine, diisopropylpentylamine, trimethylamine, lithium hydride, sodium hydride, hydrogenated Alkali metal hydrides such as potassium, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, sodium bicarbonate, An alkali metal bicarbonate such as potassium bicarbonate can be used.
  • the reaction temperature is ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
  • the reaction time is 5 minutes to 1 day, preferably 10 minutes to 12 hours.
  • the thiophene derivative (I) can be produced by the reaction of the thiophene derivative (X) amine derivative (VIII) having a leaving group.
  • the reaction can be performed in a solvent in the presence of a base.
  • the solvent is not particularly limited.
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide; ethers such as 1,4-dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile Can be used alone or in combination, and the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, metal lithium, metal sodium
  • metal Alkali metals such as potassium
  • alkali hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide
  • alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropyl Amides, potassium Isopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyl lithium, s-butyl lithium, tert-butyl lithium, etc.
  • the reaction temperature is ⁇ 10 ° C. to 200 ° C., preferably 0 ° C. to 120 ° C.
  • the reaction time is 1 hour to 72 hours, preferably
  • the borane compound (III) used in the above production method can be used as it is, or can be produced appropriately by a known method.
  • it can be produced by the following method. It is not limited.
  • a 3 represents a leaving group
  • R 6 and R 7 represent a hydrogen atom or a C 1-6 alkyl group
  • R 6 and R 7 represent Together, they may form a ring.
  • borane compound (III) is produced from compound (XI) using a metal catalyst.
  • the metal catalyst to be used is not particularly limited.
  • a ligand such as o-tritoluylphosphine, triphenylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, tri-tert-butylphosphine, and the like may be added.
  • the base to be used include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium acetate and the like, preferably potassium acetate.
  • the solvent to be used is not particularly limited.
  • ethers such as tetrahydrofuran and 1,4-dioxane
  • aromatic hydrocarbons such as toluene
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone Dimethyl sulfoxide, water and the like
  • a mixed solvent of 1,4-dioxane and water is preferred.
  • the reaction temperature is 0 ° C. to 200 ° C., preferably 80 ° C. to 150 ° C.
  • the reaction time is 1 hour to 48 hours, preferably 2 hours to 24 hours.
  • the carboxylic acid derivative (VI) used in the above production method can be used as it is, or can be appropriately produced by a known method, for example, it can be produced by the following method. It is not limited.
  • R 1 , Ring D, Q 1 , Q 4 , R 5 and Ring Y are the same as defined above, P is a protecting group, W 1 , W 2 , W 4 and W 6 are leaving groups, An aldehyde group, an amino group or a hydroxyl group is shown, and W 3 , W 5 and W 7 are C ⁇ O or NH.
  • W 1 and W 4 are a leaving group or an aldehyde group
  • W 2 and W 6 represent an amino group or a hydroxyl group
  • W 2 and W 6 are a leaving group or an aldehyde group
  • W 1 and W 4 Represents an amino group or a hydroxyl group (note that the compounds (XV) and (XV ′) represent a case where the ring Y has a substituent formed by Q 4 , R 5 and the ring D in the carboxylic acid derivative (VI)). Is shown.)]
  • Step 10 compound (XIII) or compound (XV) is produced from compound (XII), compound (XIV) or (XIV ') by a) reductive amination or b) alkylation.
  • a) Reductive amination can be carried out using a reducing reagent in a solvent in the presence or absence of an acid.
  • the dehydration operation may be performed using a Dean-Stark apparatus or the like.
  • the solvent is not particularly limited.
  • 1,2-dichloroethane, chloroform, dichloromethane, ethyl acetate, isopropyl acetate, toluene, benzene, tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, methanol, ethanol, isopropanol , Acetic acid, trifluoroacetic acid and the like can be used alone or in combination.
  • Lewis acids such as proton acids, such as propionic acid and benzoic acid, titanium tetrachloride, boron trifluoride, and stannic chloride, can be used.
  • a reducing reagent for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride,
  • borohydride reagents such as lithium triethylborohydride, lithium hydride lithium, diisopropylaluminum hydride, aluminum hydride reagents such as sodium bis (2-methoxyethoxy) aluminum hydride, metal catalyst and hydrogen source Reduction can be used.
  • a hydrogen source for catalytic reduction for example, hydrogen, cyclohexadiene, formic acid, ammonium formate and the like can be used, and as a metal catalyst, for example, palladium carbon, palladium black, palladium hydroxide, Raney nickel, platinum dioxide, platinum Black etc. can be used.
  • a metal catalyst for example, palladium carbon, palladium black, palladium hydroxide, Raney nickel, platinum dioxide, platinum Black etc. can be used.
  • Alkylation can be carried out in a solvent in the presence of a base.
  • the solvent is not particularly limited.
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone
  • dimethyl sulfoxide ethers such as 1,4-dioxane and tetrahydrofuran
  • nitriles such as acetonitrile and propionitrile Can be used alone or in combination, and the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, metal lithium, metal sodium
  • metal Alkali metals such as potassium
  • alkali hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide
  • alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate
  • lithium diisopropylamide sodium diisopropyl Amides
  • potassium Isopropylamide lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyl lithium, s-butyl lithium, tert-butyl lithium, etc.
  • the reaction temperature is ⁇ 10 ° C. to 200 ° C., and varies depending on the reaction conditions, but is preferably 0 ° C. to 120 ° C.
  • the reaction time varies from 1 hour to 72 hours depending on the reaction conditions, but is preferably 1 hour to 36 hours.
  • Step 11 There is no particular limitation on the deprotection of the protecting group, but a method that can be introduced by a generally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) or the like can be used as appropriate. However, the present invention is not limited to this.
  • the amine derivative (VIII) used in the above production method can be used as it is, or can be produced appropriately by a known method, for example, it can be produced by the following method, but is not limited thereto. Is not to be done.
  • R 1 , Ring D, Q 1 , Q 4 , R 5 and Ring Y are the same as defined above, P is a protecting group, W 1 , W 2 , W 4 and W 6 are leaving groups or An aldehyde group, an amino group, or a hydroxyl group is represented, and W 3 , W 5, and W 7 represent C ⁇ O or NH.
  • W 1 and W 4 are a leaving group or an aldehyde group
  • W 2 and W 6 represent an amino group or a hydroxyl group
  • W 2 and W 6 are a leaving group or an aldehyde group
  • W 1 and W 4 Represents an amino group or a hydroxyl group (note that compounds (XIX) and (XX) represent the case where ring Y has a substituent formed by Q 4 , R 5 and ring D in amine derivative (VIII)).
  • Step 12 compound (XVII) or compound (XIX) is produced from compound (XVI), compound (XVIII) or (XVIII ′) by a) reductive amination or b) alkylation.
  • a) Reductive amination can be carried out using a reducing reagent in a solvent in the presence or absence of an acid.
  • the dehydration operation may be performed using a Dean-Stark apparatus or the like.
  • the solvent is not particularly limited.
  • halogenated hydrocarbons such as 1,2-dichloroethane, chloroform and dichloromethane; esters such as ethyl acetate and isopropyl acetate; aromatic hydrocarbons such as toluene and benzene; tetrahydrofuran Ethers such as 1,4-dioxane; nitriles such as acetonitrile and propionitrile; alcohols such as methanol, ethanol and isopropanol; organic acids such as acetic acid and trifluoroacetic acid can be used alone or in combination. .
  • esters such as ethyl acetate and isopropyl acetate
  • aromatic hydrocarbons such as toluene and benzene
  • tetrahydrofuran Ethers such as 1,4-dioxane
  • nitriles such as acetonitrile and propionitrile
  • alcohols such as methanol, ethanol and iso
  • Lewis acids such as proton acids, such as propionic acid and benzoic acid, titanium tetrachloride, boron trifluoride, and stannic chloride, can be used.
  • a reducing reagent for example, sodium triacetoxyborohydride, tetramethylammonium borohydride tetramethylammonium, sodium cyanoborohydride, sodium borohydride, lithium borohydride, sodium trimethoxyborohydride,
  • borohydride reagents such as lithium triethylborohydride, lithium hydride lithium, diisopropylaluminum hydride, aluminum hydride reagents such as sodium bis (2-methoxyethoxy) aluminum hydride, metal catalyst and hydrogen source Reduction can be used.
  • a hydrogen source for catalytic reduction for example, hydrogen, cyclohexadiene, formic acid, ammonium formate, etc.
  • Alkylation can be carried out in a solvent in the presence of a base.
  • the solvent is not particularly limited.
  • amides such as N, N-dimethylformamide and N-methylpyrrolidone; dimethyl sulfoxide; ethers such as 1,4-dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile Can be used alone or in combination, and the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, metal lithium, metal sodium
  • metal Alkali metals such as potassium
  • alkali hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide
  • alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, sodium diisopropyl Amides, potassium Isopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, tert-butoxy sodium, tert-butoxy potassium, n-butyl lithium, s-butyl lithium, tert-butyl lithium, etc.
  • the reaction temperature is ⁇ 10 ° C. to 200 ° C., preferably 0 ° C. to 120 ° C.
  • the reaction time is 1 hour to 72 hours, preferably
  • Step 13 Although there is no particular limitation on the deprotection of the protecting group, a method that can be introduced by a generally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) or the like can be used as appropriate. However, the present invention is not limited to this.
  • Substituents on the X and Y rings in the above general formula, R 2 , R 3 and the like are oxidized, reduced with reference to methods generally used as necessary (Comprehensive Organic Transformation Second Edition, John Wiley & Sons, Inc.),
  • the desired product can be obtained by appropriate conversion by alkylation, amidation, esterification, hydrolysis, reductive amination or the like.
  • the protecting group is not particularly limited, and those that can be introduced by a generally used method (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.) can be used as appropriate.
  • the present invention is not limited to this.
  • various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between isomers.
  • a racemic mixture is obtained by a general racemic resolution method such as a method of optically resolving a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography.
  • a general racemic resolution method such as a method of optically resolving a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography.
  • the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography.
  • An optically active compound can also be produced by using an appropriate optically active raw material.
  • the TLR3, 7 and / or 9 inhibitor of the present invention, or an agent for preventing and / or treating autoimmune disease, inflammation, allergy, asthma, graft rejection and GvHD is a thiophene derivative represented by the general formula (1):
  • the salt or a solvate thereof is contained as an active ingredient and can be used as a pharmaceutical composition.
  • the compound of the present invention may be used alone, but it is usually used in combination with a pharmaceutically acceptable carrier and / or diluent.
  • the administration route is not particularly limited, but can be appropriately selected depending on the purpose of treatment.
  • any of oral preparations, injections, suppositories, inhalants and the like may be used.
  • Pharmaceutical compositions suitable for these dosage forms can be produced by utilizing known preparation methods.
  • the compound represented by the general formula (1) is a pharmaceutically acceptable excipient, and further, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, and a corrigent.
  • a flavoring agent After adding a flavoring agent, tablets, coated tablets, granules, powders, capsules and the like can be produced using conventional methods.
  • the additive may be one commonly used in the art.
  • excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like.
  • binder examples include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like.
  • disintegrant examples include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • lubricant examples include purified talc, stearate, borax, and polyethylene glycol.
  • corrigent examples include sucrose, orange peel, citric acid, tartaric acid and the like.
  • an oral solution, syrup, etc. are added to the compound represented by the general formula (1) by adding a corrigent, a buffer, a stabilizer, a corrigent and the like using a conventional method.
  • An elixir or the like can be produced.
  • the flavoring agent include those listed above.
  • the buffering agent include sodium citrate
  • examples of the stabilizing agent include tragacanth, gum arabic, and gelatin.
  • a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the compound represented by the general formula (1), and subcutaneously using a conventional method.
  • Intramuscular and intravenous injections can be manufactured.
  • the pH adjusting agent and buffer include sodium citrate, sodium acetate, sodium phosphate and the like.
  • the stabilizer include sodium pyrosulfite, EDTA (sodium edetate), thioglycolic acid, and thiolactic acid.
  • the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.
  • the isotonic agent include sodium chloride and glucose.
  • a known suppository carrier such as polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride, etc., and a surfactant (for example, , Tween (registered trademark)) and the like can be added and then manufactured using a conventional method.
  • a surfactant for example, , Tween (registered trademark)
  • the dose of the thiophene derivative represented by the general formula (1) of the present invention varies depending on age, body weight, symptom, dosage form, number of administrations, etc.
  • 0.1 mg to 1000 mg preferably 1 mg to 100 mg, more preferably 1 mg to 10 mg per day is orally or parenterally administered in one or several divided doses.
  • Step 1 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide
  • Step 2 Preparation of 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine
  • Step 3 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide N- [ 3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide (70 mg, 0.17 mmol), tetrakis (triphenylphosphine) palladium (0) (10 mg, 0.009 mmol), 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine (66 mg, 0.22 mmol), 2M carbonic acid Aqueous sodium (0.22 mL) was mixed with 1,4-dioxane (2 mL) and refluxed overnight.
  • Step 2 Preparation of 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine
  • Step 4 Preparation of methyl 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetate
  • Step 5 Preparation of 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid
  • Step 6 Preparation of 2- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetyl chloride
  • Step 7 2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2 -Il ⁇ acetamide production
  • Step 8 Preparation of 2-[(1-benzylpiperidin-4-yl) amino] -N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ acetamide
  • 2- [N- (1-Benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] -N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ acetamide (75.3 mg, 0.11 mmol) was dissolved in acetonitrile (1.1 mL), and potassium carbonate (45 mg, 0.33 mmol) and thiophenol (24.7 mg, 0.22 mmol) were added.
  • Step 2 Preparation of N- ⁇ 3- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl ⁇ -5-bromothiophene-2-carboxamide
  • Step 3 N- ⁇ 3- [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl ⁇ -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2- Production of carboxamide
  • Step 4 Preparation of N- ⁇ 3-[(1-benzylpiperidin-4-yl) amino] propyl ⁇ -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide N- ⁇ 3- With [N- (1-benzylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl ⁇ -5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide, In the same manner as in Step 8 of Example 2, the title compound (30%) was obtained as a pale brown solid.
  • Step 1 Preparation of 5-bromo-N- ⁇ 3- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl ⁇ thiophene-2-carboxamide
  • Step 2 5- [4- (4-Methylpiperazin-1-yl) phenyl] -N- ⁇ 3- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl ⁇ thiophene-2- Carboxamide production
  • Step 3 Preparation of 5- [4- (4-methylpiperazin-1-yl) phenyl] -N- ⁇ 3-[(1-methylpiperidin-4-yl) amino] propyl ⁇ thiophene-2-carboxamide 5- [4- With (4-methylpiperazin-1-yl) phenyl] -N- ⁇ 3- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] propyl ⁇ thiophene-2-carboxamide, In the same manner as in Step 8 of Example 2, the title compound (40%) was obtained as an orange solid.
  • Step 1 Preparation of methyl 2-[(1-methylpiperidin-4-yl) amino] acetate
  • Step 2 Preparation of methyl 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamide] acetate
  • Step 3 Preparation of 2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetic acid
  • Step 4 N- ⁇ 5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamide] Production of acetamide
  • Step 5 Preparation of N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2-[(1-methylpiperidin-4-yl) amino] acetamide N- ⁇ 5- With [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2- [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] acetamide, In the same manner as in Step 8 of Example 2, the title compound (2 step yield: 6%) was obtained as a black-brown oil.
  • Step 2 Preparation of N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2-[(1-methylpiperidin-4-yl) oxy] acetamide
  • 1-methyl-4 -[4- (5-aminothiophen-2-yl) phenyl] piperazine (47 mg, 0.17 mmol) was dissolved in methylene chloride (3 mL), and triethylamine (100 ⁇ L, 0.68 mmol) was added to make a solution.
  • 2-[(1-Methylpiperidin-4-yl) oxy] acetyl chloride was added in an ice bath. It returned to room temperature and stirred for 2 hours.
  • Step 2 Preparation of 4- (4-bromophenyl) -1-methyl-1,2,3,6-tetrahydropyridine
  • Step 3 Preparation of 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -1,2,3,6-tetrahydropyridine
  • Step 4 N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl]
  • thiophene-2-carboxamide N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide and 1-methyl-4- [4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -1,2,3,6-tetrahydropyridine in the same manner as in Step 3 of Example 1, The title compound (72%) was obtained as a yellow solid.
  • Example 8 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methylpiperidin-4-yl) phenyl] thiophene-2-carboxamide N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] Thiophene-2-carboxamide (10 mg, 0.02 mmol) was dissolved in ethanol (1 mL), concentrated hydrochloric acid (10 ⁇ L) and 10% palladium carbon (10 mg) were added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere.
  • Step 3 Preparation of 1-methyl-4- [4- (5-aminothiophen-2-yl) cyclohexyl] piperazine
  • Step 4 Preparation of benzyl 2-[(1-methylpiperidin-4-yl) amino] acetate
  • Step 5 Preparation of benzyl 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamide] acetate
  • Step 6 Preparation of 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetic acid
  • Step 7 2,2,2-trifluoro-N- [2-( ⁇ 5- [4- (4-methylpiperazin-1-yl) cyclohexyl] thiophen-2-yl ⁇ amino) -2-oxoethyl] -N- ( Preparation of 1-methylpiperidin-4-yl) acetamide
  • Step 1 Preparation of (E) -tert-butyl 3- (5- ⁇ [3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl ⁇ thiophen-2-yl) acrylate
  • N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromothiophene-2-carboxamide (80 mg, 0.2 mmol) is dissolved in 1,4-dioxane (2 mL) O-tritoluylphosphine (18 mg, 0.06 mmol), tert-butyl acrylate (150 ⁇ L, 1 mmol), diisopropylamine (100 ⁇ L, 0.6 mmol), tris (dibenzylideneacetone) dipalladium (0) (18 mg, 0.02 mmol) was added and the mixture was stirred at 100 ° C. for 19 hours.
  • Step 2 (E) -N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-ene
  • E -tert-butyl 3-
  • 5- ⁇ [3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl ⁇ thiophene-2 -Yl) acrylate 55 mg, 0.12 mmol
  • Step 1 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-4-methylthiophene-2-carboxamide
  • Step 2 N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -4-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide
  • Step 1 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-3-methylthiophene-2-carboxamide
  • Step 2 Preparation of N- [3-([1,4′bipiperidin] -1′-yl) propyl] -3-methyl-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-3-methylthiophene-2-carboxamide and 1-methyl-4- [4- (4,4,4 The title compound (51%) was obtained as a pale yellow solid in the same manner as in Step 3 of Example 1 using 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] piperazine.
  • Step 1 Preparation of tert-butyl 4-[(2-methoxy-2-oxoethyl) amino] piperidine-1-carboxylate
  • Step 2 Preparation of tert-butyl 4- [N- (2-methoxy-2-oxoethyl) -2-nitrophenylsulfonamido] piperidine-1-carboxylate
  • Step 3 Preparation of 2- ⁇ N- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2-nitrophenylsulfonamido ⁇ acetic acid
  • Step 4 tert-Butyl 4- ⁇ N- [2-( ⁇ 5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ amino) -2-oxoethyl] -2-nitrophenylsulfonamide ⁇ Production of piperidine-1-carboxylate
  • Step 5 Preparation of N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2- [2-nitro-N- (piperidin-4-yl) phenylsulfonamido] acetamide
  • Step 6 Preparation of N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2-[(piperidin-4-yl) amino] acetamide N- ⁇ 5- [4- Step 4 of Example 2 using (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2- [2-nitro-N- (piperidin-4-yl) phenylsulfonamido] acetamide In the same manner as the above, the title compound (61%) was obtained as a light brown solid.
  • Step 1 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5-bromo-3-methoxythiophene-2-carboxamide
  • Step 2 N- ⁇ 3-([1,4′-bipiperidin] -1′-yl) propyl ⁇ -3-methoxy-5- [4- (4-methylpiperazin-1-yl) phenyl] thiophene-2-carboxamide
  • Step 1 Preparation of 1-methyl-4- [4- (5-nitrothiophen-2-yl) phenyl] -1,2,3,6-tetrahydropyridine
  • Step 2 Preparation of 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine
  • Step 3 2,2,2-trifluoro-N- [2-( ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ amino ) -2-Oxoethyl] -N- (1-methylpiperidin-4-yl) acetamide
  • Step 4 N- ⁇ 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -2-[(1-methylpiperidin-4-yl) Preparation of amino] acetamide 2,2,2-trifluoro-N- [2-( ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- 2-yl ⁇ amino) -2-oxoethyl] -N- (1-methylpiperidin-4-yl) acetamide in the same manner as in Step 8 of Example 9, the title compound (3 step yield 55%) was obtained as a pale yellow solid.
  • Step 1 Preparation of tert-butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] piperidine-1-carboxylate
  • Step 4 tert-butyl 4- [4- (5- ⁇ 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido ⁇ thiophen-2-yl) phenoxy] piperidine- 1-carboxylate production
  • Step 5 2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- [2-oxo-2-( ⁇ 5- [4- (piperidin-4-yloxy) phenyl] thiophene-2 -Il ⁇ amino) ethyl] acetamide production
  • Step 6 2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- ⁇ 2-[(5- ⁇ 4-[(1-methylpiperidin-4-yl) oxy] phenyl ⁇ thiophene -2-yl) amino] -2-oxoethyl ⁇ acetamide
  • Step 7 Preparation of 2-[(1-methylpiperidin-4-yl) amino] -N- (5- ⁇ 4-[(1-methylpiperidin-4-yl) oxy] phenyl ⁇ thiophen-2-yl) acetamide 2, 2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- ⁇ 2-[(5- ⁇ 4-[(1-methylpiperidin-4-yl) oxy] phenyl ⁇ thiophene-2 -Il) amino] -2-oxoethyl ⁇ acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (73%) as a pale yellow solid.
  • Example 18 Production of 2- [4- (dimethylamino) piperidin-1-yl] -N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ acetamide 1 Steps 6 and 7 of Example 2 with methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine and 2- [4- (dimethylamino) piperidin-1-yl] acetic acid Similarly, the title compound (48%) was obtained as a brown solid.
  • Step 1 Production of (R) -1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylic acid
  • Step 2 Preparation of (R) -N- ⁇ 5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide Performed with (R) -1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylic acid and 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine Analogously to steps 6 and 7 of example 2, the title compound (40%) was obtained as a pale yellow solid.
  • Step 1 Production of (S) -1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylic acid
  • Step 2 Preparation of (S) -N- ⁇ 5- [4- (4-Methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -1- (1-methylpiperidin-4-yl) pyrrolidine-2-carboxamide Performed with (S) -1- (1-methylpiperazin-4-yl) pyrrolidine-2-carboxylic acid and 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine In the same manner as in Step 2 of Example 19, the title compound (49%) was obtained as a slightly yellow solid.
  • Example 21 2-[(5-hydroxypentyl) (1-methylpiperidin-4-yl) amino] -N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇
  • the title compound (89%) was obtained as a pale yellow oil in the same manner as in Step 1 of Example 5 using hydroxypentanal.
  • Step 1 Preparation of tert-butyl 4- [4- (5- ⁇ [3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl ⁇ thiophen-2-yl) phenyl] piperazine-1-carboxylate
  • Step 2 Preparation of N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene-2-carboxamide tert-Butyl 4- [ 4- (5- ⁇ [3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl ⁇ thiophen-2-yl) phenyl] piperazine-1-carboxylate was used to In the same manner as in Step 5, the title compound (87%) was obtained as a pale yellow solid.
  • Example 24 Benzyl 6- ⁇ 4- [4- (5- ⁇ [3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl ⁇ thiophen-2-yl) phenyl] piperazine-1- Yl ⁇ hexanoate N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [4- (piperazin-1-yl) phenyl] thiophene-2-carboxamide and benzyl 6 Using bromohexanoate, the title compound (69%) was obtained as a pale yellow solid in the same manner as in Example 23.
  • Step 2 Preparation of 1′-methyl-N- ⁇ 5- [4- (1-methylpiperidin-4-yl) phenyl] thiophen-2-yl ⁇ -[1,4′-bipiperidine] -4-carboxamide 1′-methyl —N- ⁇ 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -[1,4′-bipiperidine] -4-carboxamide
  • the title compound (2 step yield: 31%) was obtained as a pale yellow solid.
  • Step 1 Preparation of tert-butyl 4- [4- (5-nitrothiophen-2-yl) phenyl] piperazine-1-carboxylate
  • Step 2 Preparation of tert-butyl 4- [4- (5-aminothiophen-2-yl) phenyl] piperazine-1-carboxylate
  • Step 3 tert-butyl 4- [4- (5- ⁇ 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido ⁇ thiophen-2-yl) phenyl] piperazine- 1-carboxylate production
  • Step 4 2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) -N- [2-oxo-2-( ⁇ 5- [4- (piperazin-1-yl) phenyl] thiophene-2 -Il ⁇ amino) ethyl] acetamide production
  • Step 5 N-methyl-6- ⁇ 4- [4- (5- ⁇ 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido ⁇ thiophen-2-yl) Of phenyl] piperazin-1-yl ⁇ hexanamide
  • Step 6 Of N-methyl-6- ⁇ 4- [4- (5- ⁇ 2-[(1-methylpiperidin-4-yl) amino] acetamido ⁇ thiophen-2-yl) phenyl] piperazin-1-yl ⁇ hexanamide
  • Phenyl] piperazin-1-yl ⁇ hexanamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (2 step yield: 40%) as a brown solid.
  • Step 1 Preparation of 2-[(4-methylpiperazin-1-yl) methyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol
  • Step 2 Preparation of 2-[(4-methylpiperazin-1-yl) methyl] -4- (5-nitrothiophen-2-yl) phenol
  • Step 4 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl ⁇ thiophen-2-yl) amino] -2
  • Step 5 N- (5- ⁇ 4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl ⁇ thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4-hydroxy-3-[(4-methylpiperazin-1-yl) methyl] phenyl ⁇ thiophen-2-yl) amino] Using -2-oxoethyl ⁇ -N- (1-methylpiperidin-4-yl) acetamide in the same manner as in Step 8 of Example 9, the title compound (4 step yield: 2%) was obtained as a pale yellow solid. Got as.
  • Step 1 2-[ ⁇ 3-[(tert-Butyldimethylsilyl) oxy] propyl ⁇ (1-methylpiperidin-4-yl) amino] -N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl ] Preparation of thiophen-2-yl ⁇ acetamide
  • Step 2 2-[(3-hydroxypropyl) (1-methylpiperidin-4-yl) amino] -N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ acetamide
  • Step 1 Preparation of 2- (4-methylpiperazin-1-yl) -N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetamide
  • Step 2 Preparation of 2- (4-methylpiperazin-1-yl) -N- [4- (5-nitrothiophen-2-yl) phenyl] acetamide
  • Step 3 Preparation of N- [4- (5-aminothiophen-2-yl) phenyl] -2- (4-methylpiperazin-1-yl) acetamide
  • Step 4 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4- [2- (4-methylpiperazin-1-yl) acetamido] phenyl ⁇ thiophen-2-yl) amino] -2-oxoethyl ⁇ Production of —N- (1-methylpiperidin-4-yl) acetamide
  • Step 5 Preparation of 2- (4-methylpiperazin-1-yl) -N- [4- (5- ⁇ 2-[(1-methylpiperidin-4-yl) amino] acetamido ⁇ thiophen-2-yl) phenyl] acetamide 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4- [2- (4-methylpiperazin-1-yl) acetamido] phenyl ⁇ thiophen-2-yl) amino] -2-oxoethyl ⁇ -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (66%) as a yellow solid.
  • Step 1 Preparation of 3- (5-bromo-1H-indol-1-yl) -N, N-dimethylpropan-1-amine
  • Step 2 Of N, N-dimethyl-3- [5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indol-1-yl] propan-1-amine Manufacturing
  • Step 3 Preparation of N, N-dimethyl-3- [5- (5-nitrothiophen-2-yl) -1H-indol-1-yl] propan-1-amine
  • Step 4 Preparation of 5- ⁇ 1- [3- (dimethylamino) propyl] -1H-indol-5-yl ⁇ thiophen-2-amine
  • Step 5 N- ⁇ 2-[(5- ⁇ 1- [3- (dimethylamino) propyl] -1H-indol-5-yl ⁇ thiophen-2-yl) amino] -2-oxoethyl ⁇ -2,2,2- Preparation of trifluoro-N- (1-methylpiperidin-4-yl) acetamide
  • Step 6 N- (5- ⁇ 1- [3- (dimethylamino) propyl] -1H-indol-5-yl ⁇ thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide
  • -trifluoro-N- (1-methylpiperidin-4-yl) acetamide the title compound (3 step yield: 39%) was obtained as a gray solid in the same manner as in Step 8 of Example 9.
  • Step 1 Preparation of tert-butyl [1-( ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ amino) -1-oxo-3-phenylpropan-2-yl] carbamate
  • Example 1 Step 1 of Example 1 with 1-methyl-4- [4- (5-aminothiophen-2-yl) phenyl] piperazine and 2-[(tert-butoxycarbonyl) amino] -3-phenylpropanoic acid. In the same manner as above, the title compound (crude) was obtained.
  • Step 2 Preparation of 2-amino-N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -3-phenylpropanamide
  • Step 3 Preparation of N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2-[(1-methylpiperidin-4-yl) amino] -3-phenylpropanamide Examples using 2-amino-N- ⁇ 5- [4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -3-phenylpropanamide and 1-methyl-4-piperidone In the same manner as in Step 1 of 5, the title compound (52%) was obtained as a pale yellow amorphous.
  • Example 32 N- ⁇ 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -1- (1-methylpiperidine-4- Yl) Preparation of pyrrolidine-3-carboxamide 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and 1- (1-methylpiperidine- The title compound (4%) was obtained as a yellow solid in the same manner as in Steps 6 and 7 of Example 2 using 4-yl) pyrrolidine-3-carboxylic acid.
  • Example 34 4-methyl-N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -2-[(1- Methylpiperidin-4-yl) amino] pentanamide
  • Step 1 tert-butyl [4-methyl-1-( ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ amino) -1- Of Oxopentan-2-yl] carbamate
  • Step 2 Preparation of 2-amino-4-methyl-N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ pentanamide
  • Step 3 4-methyl-N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -2-[(1-methylpiperidine- Preparation of 4-yl) amino] pentanamide 2-amino-4-methyl-N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene- Using 2-yl ⁇ pentanamide and 4-methyl-1-piperidone, the title compound (3%) was obtained as a pale yellow amorphous in the same manner as in Step 1 of Example 5.
  • Step 1 tert-Butyl 4- [4- (5- ⁇ 3- [1- (tert-butoxycarbonyl) piperidin-4-yl] ureido ⁇ thiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -Production of carboxylates
  • Step 2 Preparation of 1- (piperidin-4-yl) -3- ⁇ 5- [4- [1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ urea tert-butyl 4- [4- (5- ⁇ 3- [1- (tert-butoxycarbonyl) piperidin-4-yl] ureido ⁇ thiophen-2-yl) phenyl] -5,6-dihydropyridine-1 (2H) -carboxylate (58 mg, 0.1 mmol) was dissolved in methylene chloride (2 mL), and TFA (2 mL) was added under ice cooling, followed by stirring for 1 hour.
  • Example 36 4-methoxy-N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -2-[(1- Methylpiperidin-4-yl) amino] butanamide
  • Step 1 (9H-Fluoren-9-yl) methyl [4-methoxy-1-( ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2- Yil ⁇ amino) -1-oxobutan-2-yl] carbamate
  • Step 2 Preparation of 2-amino-4-methoxy-N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ butanamide
  • Step 3 4-methoxy-N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -2-[(1-methylpiperidine- Preparation of 4-yl) amino] butanamide 2-amino-4-methoxy-N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-2 The title compound (10%) was obtained as a pale yellow amorphous in the same manner as in Step 1 of Example 5 using -yl ⁇ butanamide.
  • Step 1 Preparation of 1- [2,5-dimethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -4-methylpiperazine
  • Step 3 Preparation of 5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-amine
  • Step 4 N- [2-( ⁇ 5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ amino) -2-oxoethyl] -2,2,2- Preparation of trifluoro-N- (1-methylpiperidin-4-yl) acetamide
  • Step 5 Of N- ⁇ 5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2-[(1-methylpiperidin-4-yl) amino] acetamide Production N- [2-( ⁇ 5- [2,5-dimethoxy-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ amino) -2-oxoethyl] -2,2,2 Using -trifluoro-N- (1-methylpiperidin-4-yl) acetamide, the title compound (75%) was obtained as a brown amorphous in the same manner as in Step 8 of Example 9.
  • Step 2 Preparation of 5- (5-aminothiophen-2-yl) -2- (4-methylpiperazin-1-yl) benzonitrile
  • Step 3 N- [2-( ⁇ 5- [3-Cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ amino) -2-oxoethyl] -2,2,2-trifluoro Preparation of —N- (1-methylpiperidin-4-yl) acetamide
  • Step 4 Preparation of N- ⁇ 5- [3-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2-[(1-methylpiperidin-4-yl) amino] acetamide N -[2-( ⁇ 5- [3-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ amino) -2-oxoethyl] -2,2,2-trifluoro- The title compound (86%) was obtained as a pale-yellow crystalline powder in the same manner as in Step 8 of Example 9 using N- (1-methylpiperidin-4-yl) acetamide.
  • Step 1 Preparation of 2- (4-methylpiperazin-1-yl) -5- (5-nitrothiophen-2-yl) benzamide
  • Step 2 Preparation of 5- (5-aminothiophen-2-yl) -2- (4-methylpiperazin-1-yl) benzamide
  • Step 3 2- (4-Methylpiperazin-1-yl) -5- (5- ⁇ 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido ⁇ thiophene-2 -Il) Production of benzamide
  • Step 4 Preparation of 2- (4-methylpiperazin-1-yl) -5- (5- ⁇ 2-[(1-methylpiperidin-4-yl) amino] acetamido ⁇ thiophen-2-yl) benzamide
  • 2- (4- Methylpiperazin-1-yl) -5- (5- ⁇ 2- [2,2,2-trifluoro-N- (1-methylpiperidin-4-yl) acetamido] acetamido ⁇ thiophen-2-yl) benzamide
  • Step 1 tert-Butyl 4- ⁇ 4- [5- (3-([1,4′-bipiperidin] -1′-yl) propanamido) thiophen-2-yl] phenyl ⁇ -5,6-dihydropyridine-1 (2H ) -Carboxylate production
  • Step 2 3-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇
  • the title compound (93%) was obtained as a pale gray solid in the same manner as in Step 5 of Example 13 using -1 (2H) -carboxylate.
  • Example 41 3-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl
  • thiophen-2-yl ⁇ propanamide 3-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridine-4] -Iyl) phenyl] thiophen-2-yl ⁇ propanamide and formaldehyde were used in the same manner as in Step 1 of Example 5 to obtain the title compound (58%) as a yellow solid.
  • Example 42 Benzyl 2- [4- (4- ⁇ 5- [3-([1,4′-bipiperidin] -1′-yl) propanamido] thiophen-2-yl ⁇ phenyl) -5,6-dihydropyridine
  • -1 (2H) -yl] acetate 3-([1,4'-bipiperidin] -1'-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridine-4 -Iyl) phenyl] thiophen-2-yl ⁇ propanamide and benzyl chloroacetate were used in the same manner as in Example 23 to obtain the title compound (77%) as a pale yellow solid.
  • Example 43 3-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl
  • Preparation of thiophen-2-yl ⁇ propanamide 3-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridine-4] -Iyl) phenyl] thiophen-2-yl ⁇ propanamide and acetone were used in the same manner as in Step 1 of Example 5 to obtain the title compound (5%) as a pale yellow solid.
  • Step 1 tert-Butyl 4- ⁇ 4- [5- (2-([1,4′-bipiperidin] -1′-yl) acetamido) thiophen-2-yl] phenyl ⁇ -5,6-dihydropyridine-1 (2H) -Production of carboxylates
  • Step 2 2-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ Production of acetamide
  • Step 3 2-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-
  • the title compound (2 step yield: 85%) was obtained as a yellow solid in the same manner as in Step 1 of Example 5 using thiophen-2-yl ⁇ acetamide and formaldehyde.
  • Step 1 tert-Butyl 4- ⁇ 4- [5- (4-([1,4′-bipiperidin] -1′-yl) butanamido) thiophen-2-yl] phenyl ⁇ -5,6-dihydropyridine-1 (2H) -Production of carboxylates
  • Step 2 4-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ Production of butanamide
  • Step 3 4-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-
  • 2-yl ⁇ butanamide 4-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl
  • the title compound (2 step yield: 54%) was obtained as a yellow solid in the same manner as in Step 1 of Example 5 using thiophen-2-yl ⁇ butanamide and formaldehyde.
  • Step 1 tert-Butyl 4- ⁇ 4- [5- (5-([1,4′-bipiperidin] -1′-yl) pentanamido) thiophen-2-yl] phenyl ⁇ -5,6-dihydropyridine-1 (2H ) -Carboxylate production
  • Step 2 5-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ Production of pentanamide
  • Step 3 5-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-
  • 2-yl ⁇ pentanamide 5-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) Phenyl] thiophen-2-yl ⁇ pentanamide and formaldehyde were used in the same manner as in Step 1 of Example 5 to obtain the title compound (2 step yield: 52%) as a yellow solid.
  • Step 1 tert-Butyl 4- ⁇ 4- [5- (6-([1,4′-bipiperidin] -1′-yl) hexanamido) thiophen-2-yl] phenyl ⁇ -5,6-dihydropyridine-1 (2H ) -Carboxylate production
  • Step 2 6-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ Hexanamide production
  • Step 3 6-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophene-
  • 2-yl ⁇ hexaneamide 6-([1,4′-bipiperidin] -1′-yl) -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) Phenyl] thiophen-2-yl ⁇ hexanamide and formaldehyde were used in the same manner as in Step 1 of Example 5 to obtain the title compound (2 step yield: 79%) as a yellow solid.
  • Step 1 Preparation of 5- (4-methylpiperazin-1-yl) -2- (5-nitrothiophen-2-yl) benzonitrile
  • Step 3 N- [2-( ⁇ 5- [2-Cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ amino) -2-oxoethyl] -2,2,2-trifluoro Preparation of —N- (1-methylpiperidin-4-yl) acetamide
  • Step 4 Preparation of N- ⁇ 5- [2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ -2-[(1-methylpiperidin-4-yl) amino] acetamide N -[2-( ⁇ 5- [2-cyano-4- (4-methylpiperazin-1-yl) phenyl] thiophen-2-yl ⁇ amino) -2-oxoethyl] -2,2,2-trifluoro- Using N- (1-methylpiperidin-4-yl) acetamide, the title compound (81%) was obtained as a yellow amorphous in the same manner as in Step 8 of Example 9.
  • Step 1 Production of 4- (5-nitrothiophen-2-yl) phenol
  • Step 2 Preparation of 1-methyl-4- ⁇ 2- [4- (5-nitrothiophen-2-yl) phenoxy] ethyl ⁇ piperazine
  • Step 3 Preparation of 5- ⁇ 4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl ⁇ thiophen-2-amine
  • Step 4 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl ⁇ thiophen-2-yl) amino] -2-oxoethyl ⁇ Production of —N- (1-methylpiperidin-4-yl) acetamide
  • Step 5 Preparation of N- (5- ⁇ 4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl ⁇ thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl ⁇ thiophen-2-yl) amino] -2-oxoethyl ⁇ -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (3 steps, yield 16%) as a yellow amorphous substance.
  • Step 1 Preparation of 1-methyl-4- ⁇ 4- [4- (5-nitrothiophen-2-yl) phenoxy] butyl ⁇ piperazine
  • Step 2 Preparation of 5- ⁇ 4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl ⁇ thiophen-2-amine
  • Step 3 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl ⁇ thiophen-2-yl) amino] -2-oxoethyl ⁇ Production of —N- (1-methylpiperidin-4-yl) acetamide
  • Step 4 Preparation of N- (5- ⁇ 4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl ⁇ thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl ⁇ thiophen-2-yl) amino] -2-oxoethyl ⁇ -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (3 step yield: 13%) as a yellow amorphous.
  • Step 1 Preparation of 1-methyl-4- ⁇ 5- [4- (5-nitrothiophen-2-yl) phenoxy] pentyl ⁇ piperazine
  • Step 2 Preparation of 5- (4- ⁇ [5- (4-Methylpiperazin-1-yl) pentyl] oxy ⁇ phenyl) thiophen-2-amine
  • Step 4 N- [5- (4- ⁇ [5- (4-Methylpiperazin-1-yl) pentyl] oxy ⁇ phenyl) thiophen-2-yl] -2-[(1-methylpiperidin-4-yl) amino]
  • Amino ⁇ -2-oxoethyl) -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to give the title compound (3 step yield 14%) as a yellow amorphous substance. Obtained.
  • Step 1 tert-butyl 4- (4- ⁇ 5- [2-( ⁇ [1- (tert-butoxycarbonyl) piperidin-4-yl] methyl ⁇ amino) acetamido] thiophen-2-yl ⁇ phenyl) -5,6- Preparation of dihydropyridine-1 (2H) -carboxylate
  • Step 2 tert-butyl 4- (4- ⁇ 5- [2- (N- ⁇ [1- (tert-butoxycarbonyl) piperidin-4-yl] methyl ⁇ -2,2,2-trifluoroacetamido) acetamido] thiophene- Preparation of 2-yl ⁇ phenyl) -5,6-dihydropyridine-1 (2H) -carboxylate
  • Step 3 2,2,2-trifluoro-N- [2-oxo-2-( ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ amino ) Ethyl] -N- (piperidin-4-ylmethyl) acetamide
  • Step 4 2,2,2-trifluoro-N- [2-( ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ amino ) -2-Oxoethyl] -N-[(1-methylpiperidin-4-yl) methyl] acetamide
  • Step 5 N- ⁇ 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -2- ⁇ [(1-methylpiperidin-4-yl ) Preparation of methyl] amino ⁇ acetamide 2,2,2-trifluoro-N- [2-( ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] ] Thiophen-2-yl ⁇ amino) -2-oxoethyl] -N-[(1-methylpiperidin-4-yl) methyl] acetamide in the same manner as in Step 8 of Example 9, the title compound (84 %) As a pale yellow solid.
  • Step 2 Preparation of 5- ⁇ 4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophen-2-amine
  • Step 3 Preparation of N- (5- ⁇ 4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophen-2-yl) -5- (pyrrolidin-1-yl) pentanamide 5- ⁇ 4- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophen-2-amine, 5-bromopentanoyl chloride and pyrrolidine were used in the same manner as in Step 1 of Example 40 to obtain the title compound (15 %) As a tan solid.
  • Example 54 5-([1,4′-bipiperidin] -1′-yl) -N- (5- ⁇ 4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophene-2- Yl) Preparation of pentanamide Using 5- ⁇ 4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophen-2-amine, 5-bromopentanoyl chloride and 1,4′-bipiperidine The title compound (12%) was obtained as a brown amorphous product in the same manner as in Step 1 of Example 40.
  • Example 55 Preparation of N- (5- ⁇ 4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophen-2-yl) -5- (piperidin-1-yl) pentanamide 5- ⁇ 4- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophen-2-amine, 5-bromopentanoyl chloride and piperidine were used in the same manner as in Step 1 of Example 40 to obtain the title. The compound (15%) was obtained as a pale yellow solid.
  • Step 1 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophen-2-yl) amino] -2-oxoethyl ⁇ Production of —N- (1-methylpiperidin-4-yl) acetamide
  • Step 2 Preparation of N- (5- ⁇ 4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophen-2-yl) -2-[(1-methylpiperidin-4-yl) amino] acetamide 2,2,2-trifluoro-N- ⁇ 2-[(5- ⁇ 4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl ⁇ thiophen-2-yl) amino] -2-oxoethyl ⁇ -N- (1-methylpiperidin-4-yl) acetamide was used in the same manner as in Step 8 of Example 9 to obtain the title compound (2 step yield: 4%).
  • Step 1 tert-Butyl 4- [4- (5- ⁇ [3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl ⁇ thiophen-2-yl) -1H-pyrazol-1-yl] piperidine 1-carboxylate production
  • Step 2 N- [3-([1,4′-bipiperidin] -1′-yl) propyl] -5- [1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl] thiophene-2
  • carboxamide tert-butyl 4- [4- (5- ⁇ [3-([1,4′-bipiperidin] -1′-yl) propyl] carbamoyl ⁇ thiophen-2-yl) -1H-pyrazole-1 -Il] piperidine-1-carboxylate (98 mg, 0.17 mmol) was dissolved in methylene chloride (2 mL), TFA (0.5 mL) was added and stirred for 0.5 h, the reaction mixture was concentrated, and the residue was Obtained.
  • Example 58 6-[(Dimethylamino) methyl] -N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ nicotine Preparation of Amides Using 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and 6-[(dimethylamino) methyl] nicotinic acid In the same manner as in Step 1 of Example 1, the title compound (46%) was obtained as a yellow solid.
  • Example 59 N- ⁇ 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -4- (4-methylpiperazine-1- Yl) Preparation of benzamide 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-amine and 4- (4-methylpiperazin-1-yl) The title compound (4%) was obtained as a yellow solid in the same manner as in Step 1 of Example 1 using benzoic acid.
  • Step 1 Preparation of methyl 4- ⁇ [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] methyl ⁇ benzoate
  • Step 2 Preparation of 4- ⁇ [N- (1-methylpiperidin-4-yl) -2-nitrophenylsulfonamido] methyl ⁇ benzoic acid
  • Step 3 N- ⁇ 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -4- ⁇ [N- (1-methylpiperidine-4 -Il) -2-Nitrophenylsulfonamido] methyl ⁇ benzamide
  • Step 4 N- ⁇ 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -4- ⁇ [(1-methylpiperidin-4-yl ) Preparation of amino] methyl ⁇ benzamide N- ⁇ 5- [4- (1-Methyl-1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ -4- ⁇ [N -(1-Methylpiperidin-4-yl) -2-nitrophenylsulfonamido] methyl ⁇ benzamide was used in the same manner as in Step 8 of Example 2 to give the title compound (2 step yield: 11%) as an orange solid. Got as.
  • Step 1 Preparation of methyl 2- ⁇ 6-[(dimethylamino) methyl] pyridin-3-yl ⁇ acetate
  • Step 2 Production of 2- ⁇ 6-[(dimethylamino) methyl] pyridin-3-yl ⁇ acetic acid
  • Step 3 tert-butyl 4- ⁇ 4- [5- (2- ⁇ 6-[(dimethylamino) methyl] pyridin-3-yl ⁇ acetamido) thiophen-2-yl] phenyl ⁇ -5,6-dihydropyridine-1 (2H ) -Carboxylate production
  • Step 4 2- ⁇ 6-[(Dimethylamino) methyl] pyridin-3-yl ⁇ -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridin-4-yl) phenyl] thiophen-2-yl ⁇ Production of Acetamide tert-Butyl 4- ⁇ 4- [5- (2- ⁇ 6-[(Dimethylamino) methyl] pyridin-3-yl ⁇ acetamido) thiophen-2-yl] phenyl ⁇ -5,6-dihydropyridine The title compound (2 step yield: 24%) was obtained as an orange solid in the same manner as in Step 5 of Example 13 using -1 (2H) -carboxylate.
  • Example 62 2- ⁇ 6-[(Dimethylamino) methyl] pyridin-3-yl ⁇ -N- ⁇ 5- [4- (1-methyl-1,2,3,6-tetrahydropyridin-4-yl) Preparation of phenyl] thiophen-2-yl ⁇ acetamide 2- ⁇ 6-[(Dimethylamino) methyl] pyridin-3-yl ⁇ -N- ⁇ 5- [4- (1,2,3,6-tetrahydropyridine- 4-yl) phenyl] thiophen-2-yl ⁇ acetamide and formaldehyde were used as in Step 1 of Example 5 to give the title compound (71%) as an orange solid.
  • Step 1 Preparation of 1-methyl-4- [5- (5-nitrothiophen-2-yl) pyridin-2-yl] piperazine
  • Step 2 Preparation of 5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-amine
  • Step 4 Production of N- ⁇ 5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-yl ⁇ -2-[(1-methylpiperidin-4-yl) amino] acetamide 2 , 2,2-trifluoro-N- [2-( ⁇ 5- [6- (4-methylpiperazin-1-yl) pyridin-3-yl] thiophen-2-yl ⁇ amino) -2-oxoethyl]- The title compound (quantitative) was obtained as a pale brown solid in the same manner as in Step 8 of Example 9 using N- (1-methylpiperidin-4-yl) acetamide.
  • TLR9 activation inhibition test using TLR9-expressing reporter cells 1) Establishment of TLR9-expressing reporter cells Human TLR9-expressing cells are cells obtained by expressing human TLR9 in human fetal kidney cell line, Invivogen. (HTLR9 / 293xL). hTLR9 / 293xL was subcultured using Dulbecco's modified Eagle medium (DMEM (sigma)) containing 10% fetal bovine serum, penicillin, and streptomycin. PGL4.28 (Promega) in which a firefly luciferase gene was linked to the NF ⁇ B recognition sequence four times was introduced by lipofection using Fugene6 (Roche).
  • DMEM Dulbecco's modified Eagle medium
  • Hygromycin and blasticidin resistant cell clones were selected and used as TLR9 expression reporter cells (hTLR9 NF ⁇ B-luc / 293xL). 2) TLR9 plated at activation inhibition test hTLR9 NF ⁇ B-luc / 96 well-white 293xL microtiter plate 1.0 ⁇ 10 4 / 80 ⁇ L, 37 °C in CO 2 incubator, and cultured overnight. A test compound (10 ⁇ L) diluted with DMEM was added to a final concentration of 0.01, 0.03, 0.1, 0.3, 1 ⁇ M. One hour later, CpG-B DNA (ODN2006) (Invivogen) as a TLR9 ligand was added to a final concentration of 1 ⁇ M (10 ⁇ L).
  • Luciferase activity was measured as TLR9 activity after incubation in a CO 2 incubator for a total of 100 ⁇ L for 4 hours. Luciferase activity was measured by adding 60 ⁇ L of Bright Glo (Promega) and measuring the amount of luminescence with a multi-microplate reader ARVO (Perkin Elmer). The 50% inhibitory concentration (IC 50 value) of each test compound was calculated with the luciferase activity when no test compound was added as 100%.
  • TLR7 activation inhibition test using TLR7-expressing reporter cells 1) Establishment of TLR7-expressing reporter cells Human TLR7-expressing cells were obtained by expressing cells expressing human TLR7 in human fetal kidney cell line, Invivogen. (HTLR7 / 293xL). hTLR7 / 293xL was subcultured using Dulbecco's modified Eagle medium (DMEM (sigma)) containing 10% fetal bovine serum, penicillin, and streptomycin. PGL4.28 (Promega) in which a firefly luciferase gene was linked to the NF ⁇ B recognition sequence four times was introduced by lipofection using Fugene6 (Roche).
  • DMEM Dulbecco's modified Eagle medium
  • Hygromycin and blasticidin resistant cell clones were selected and used as TLR7 expression reporter cells (hTLR7 NF ⁇ B-luc / 293 ⁇ L). 2) The TLR7 activation Inhibition Test hTLR7 NF ⁇ B-luc / 293xL plated at 1.0 ⁇ 10 4 / 80 ⁇ L in a 96 well white microtiter plate, 37 ° C. in a CO 2 incubator, and cultured overnight. A test compound (10 ⁇ L) diluted with DMEM was added to a final concentration of 0.03, 0.1, 0.3, 1, 3, 10 ⁇ M. One hour later, Imiquimod (Invivogen), a TLR7 ligand, was added to a final concentration of 10 ⁇ M (10 ⁇ L).
  • Luciferase activity was measured as TLR7 activity after incubation in a CO 2 incubator for a total of 100 ⁇ L for 4 hours. Luciferase activity was measured by adding 60 ⁇ L of Bright Glo (Promega) and measuring the amount of luminescence with a multi-microplate reader ARVO (Perkin Elmer). The 50% inhibitory concentration (IC 50 value) of each test compound was calculated with the luciferase activity when no test compound was added as 100%. 3) Results Table 2 shows the activity values (IC 50 values) of the compounds obtained in the above examples.
  • the compound of the present invention has a strong TLR7 and 9 inhibitory action. Therefore, the thiophene derivative represented by the general formula (1) of the present invention is used as a TLR7 and 9 inhibitor as a disease associated with activation of TLR7 and 9 signals such as RA, SLE, SS, MS, IBD, psoriasis. It has been found to be useful as an active ingredient for preventive and therapeutic agents for autoimmune diseases such as osteoarthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection and GvHD.
  • autoimmune diseases such as osteoarthritis, Behcet's syndrome, vasculitis, inflammation, allergy, asthma, graft rejection and GvHD.
  • mice Male DBA / 1J mice (Nippon Charles River Co., Ltd.) were used. The body weight of 7-week-old DBA / 1J mice was measured, and grouping was performed using a single-block blocking assignment using this as an index.
  • the group composition was the control group (administration medium (0.5% hydroxymethylpropylcellulose aqueous solution) administration group), the compound of Example 5 administered with 25 mg / kg, and the compound of Example 5 administered with 50 mg / kg.
  • test method A 0.2% type 2 collagen solution is prepared by mixing 0.3% type 2 collagen solution (collagen technical workshop) and physiological saline (Otsuka Pharmaceutical) in a ratio of 2: 1. did. Next, an equal amount of 0.2% type 2 collagen solution and Adjuvant Complete Freund (DIFCO) were mixed, and a first-sensitized emulsion was prepared with a handy microhomogenizer NS-310E (Microtech Nithion) under ice cooling. After shaving the ridges of the animals with clippers, 0.05 mL each of the first sensitizing emulsion was intradermally administered to the left and right sides of the ridges. After the first sensitization, the drug solution was orally administered once a day until 34 days after the first sensitization (14 days after the additional sensitization).
  • DIFCO Adjuvant Complete Freund
  • Additional sensitization was performed by the following procedure 20 days after the first sensitization.
  • a 0.2% type 2 collagen solution was prepared by mixing 0.3% type 2 collagen solution and physiological saline at a ratio of 2: 1. Then, an equal amount of 0.2% type 2 collagen solution and Adjuvant Incomplete Freund (DIFCO) were mixed, and an additional sensitive emulsion was prepared with a handy microhomogenizer NS-310E under ice cooling. Additional sensitization was performed by administering 0.1 mL of the prepared additional sensitizing emulsion into the ridge skin to induce arthritis.
  • DIFCO Adjuvant Incomplete Freund
  • the primary endpoint, limb swelling, was determined by arthritis score by three judges in a blinded trial, 3 times in total: initial assessment 7 days after additional sensitization, intermediate assessment 10 days later, and final assessment 14 days later.
  • the arthritis score was determined.
  • As the evaluation criteria for swelling the following four criteria were applied to each limb, and the total of the limbs was used as the individual arthritis score.
  • plasma anti-type 2 collagen IgG antibody titer was measured by ELISA using an orbital blood sample 15 days after additional sensitization.
  • FIG. 6 is a graph showing changes over time in arthritis scores of a mouse collagen-induced arthritis model in a control group (drug non-administration group) and the compound of Example 5 in a 25 mg / kg administration group and a 50 mg / kg administration group.
  • the control group an increase in the arthritis score was observed after 7 days from the additional sensitization.
  • the administration group of the compound of Example 5 showed a significant inhibitory effect suggesting dose dependency at a dose of 50 mg / kg.
  • ** indicates that the risk rate is less than 1% (p ⁇ 0.01) in Steel's multiple comparison test using the control group as a comparison control.
  • FIG. 2 shows the average value of anti-type 2 collagen IgG antibody titer 15 days after the additional sensitization.
  • FIG. 2 In contrast to the control group, the 25 and 50 mg / kg administration groups of the compound of Example 5 showed a significant inhibitory effect suggesting dose dependency.
  • * and ** indicate a risk rate of less than 5% (p ⁇ 0.05) and less than 1% (p ⁇ 0.01), respectively, in Steel's multiple comparison test using the control group as a comparison control. Indicates that
  • the compound of Example 5 is effective as a therapeutic agent for rheumatoid arthritis.
  • the present invention for the first time finds that the thiophene derivative represented by the general formula (1) or a salt thereof, or a solvate thereof has an excellent TLR3, 7 and / or 9 inhibitory action, and autoimmunity.
  • the present invention provides a preventive and / or therapeutic agent for cardiomyopathy due to disease, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis.
  • the present invention provides a preventive and / or therapeutic agent for cardiomyopathy caused by autoimmune disease, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD) or sepsis, and is useful in the pharmaceutical industry. Has industrial applicability.

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Abstract

La présente invention concerne un nouveau composé qui inhibe au moins un récepteur choisi dans le groupe constitué par TLR3, TLR7 et TLR9 et qui présente une excellente activité préventive et thérapeutique contre une maladie auto-immune, une inflammation, une allergie et similaire. La présente invention concerne un composé représenté par la formule générale suivante (1) : [où X est un carbocycle ou un hétérocycle facultativement substitué formé facultativement par l'intermédiaire de groupes alkylène ou alcénylène ; l'anneau Y est un carbocycle ou hétérocycle facultativement substitué ; R2 et R3 sont identiques ou différents et sont un atome d'hydrogène, un groupe alkyle en C1-6 ou un groupe alkyloxy en C1-6 ; Q1 est une liaison ou un groupe alkylène ou un groupe alcénylène en C2-6 facultativement substitué ; R1 est une liaison, un atome d'oxygène ou un groupe NH facultativement substitué ; et l'association de q, m, et n est (q, m, n) = (0, 1, 0), (0, 0, 1), (0, 1, 1), (1, 1, 0), (1, 0, 1) ou (1, 1, 1)] ; ou son sel ou le solvat de celui-ci.
PCT/JP2013/062049 2012-04-25 2013-04-24 Dérivé de thiophène ayant une activité inhibitrice de tlr WO2013161871A1 (fr)

Applications Claiming Priority (4)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
JP2023537909A (ja) * 2020-08-21 2023-09-06 カナプ セラピューティクス インコーポレイテッド プロスタグランジンｅ２受容体に対して阻害活性を有する新規化合物及びその使用

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939332A (en) * 1998-02-27 1999-08-17 Roche Diagnostics Corp. Phencyclidine analogs for immunoassay
JPH11322711A (ja) * 1998-04-15 1999-11-24 Pfizer Prod Inc 複素環式カルボキサミド
WO2001074791A1 (fr) * 2000-03-31 2001-10-11 Yamanouchi Pharmaceutical Co., Ltd. Derives de diazepane ou sels desdits composes
JP2002121153A (ja) * 2000-09-06 2002-04-23 Pfizer Prod Inc 抑うつ及び不安のための併合療法
JP2004506734A (ja) * 2000-08-21 2004-03-04 ファルマシア・アンド・アップジョン・カンパニー 疾患治療用のキヌクリド置換ヘテロアリール部分
JP2005504058A (ja) * 2001-08-24 2005-02-10 ファルマシア アンド アップジョン カンパニー リミティド ライアビリティー カンパニー 疾患の治療のための置換ヘテロアリール−７−アザ［２．２．１］ビシクロヘプタン
JP2006505530A (ja) * 2002-09-02 2006-02-16 アストラゼネカ・アクチエボラーグ アルファ−７ニコチン受容体作用剤およびスタチンの組み合わせ
JP2007529490A (ja) * 2004-03-19 2007-10-25 アロー セラピューティクス リミテッド Ｒｓｖ感染の処置または予防用ベンゾジアゼピン
JP2007531757A (ja) * 2004-03-30 2007-11-08 カイロン コーポレイション 抗癌剤としての置換チオフェン誘導体
JP2008531723A (ja) * 2005-03-03 2008-08-14 アムジエン・インコーポレーテツド フタラジン、アザ及びジアザフタラジン化合物並びに使用方法
JP2010508288A (ja) * 2006-10-27 2010-03-18 ブリストル−マイヤーズ スクイブ カンパニー キナーゼ阻害剤として有用なヘテロサイクリックアミド化合物
JP2010513444A (ja) * 2006-12-21 2010-04-30 アストラゼネカ アクチボラグ 新規化合物
JP2011506358A (ja) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト 新規２−置換チアゾール−４−カルボキサミド誘導体、それらの製造および医薬としての使用
JP2011506362A (ja) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト ２−アリールチアゾール−４−カルボキサミド誘導体、それらの製造および医薬としての使用
JP2011506361A (ja) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト 新規２−ヘタリールチアゾール−４−カルボキサミド誘導体、それらの製造および医薬としての使用

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939332A (en) * 1998-02-27 1999-08-17 Roche Diagnostics Corp. Phencyclidine analogs for immunoassay
JPH11322711A (ja) * 1998-04-15 1999-11-24 Pfizer Prod Inc 複素環式カルボキサミド
WO2001074791A1 (fr) * 2000-03-31 2001-10-11 Yamanouchi Pharmaceutical Co., Ltd. Derives de diazepane ou sels desdits composes
JP2004506734A (ja) * 2000-08-21 2004-03-04 ファルマシア・アンド・アップジョン・カンパニー 疾患治療用のキヌクリド置換ヘテロアリール部分
JP2002121153A (ja) * 2000-09-06 2002-04-23 Pfizer Prod Inc 抑うつ及び不安のための併合療法
JP2005504058A (ja) * 2001-08-24 2005-02-10 ファルマシア アンド アップジョン カンパニー リミティド ライアビリティー カンパニー 疾患の治療のための置換ヘテロアリール−７−アザ［２．２．１］ビシクロヘプタン
JP2006505530A (ja) * 2002-09-02 2006-02-16 アストラゼネカ・アクチエボラーグ アルファ−７ニコチン受容体作用剤およびスタチンの組み合わせ
JP2007529490A (ja) * 2004-03-19 2007-10-25 アロー セラピューティクス リミテッド Ｒｓｖ感染の処置または予防用ベンゾジアゼピン
JP2007531757A (ja) * 2004-03-30 2007-11-08 カイロン コーポレイション 抗癌剤としての置換チオフェン誘導体
JP2008531723A (ja) * 2005-03-03 2008-08-14 アムジエン・インコーポレーテツド フタラジン、アザ及びジアザフタラジン化合物並びに使用方法
JP2010508288A (ja) * 2006-10-27 2010-03-18 ブリストル−マイヤーズ スクイブ カンパニー キナーゼ阻害剤として有用なヘテロサイクリックアミド化合物
JP2010513444A (ja) * 2006-12-21 2010-04-30 アストラゼネカ アクチボラグ 新規化合物
JP2011506358A (ja) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト 新規２−置換チアゾール−４−カルボキサミド誘導体、それらの製造および医薬としての使用
JP2011506362A (ja) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト ２−アリールチアゾール−４−カルボキサミド誘導体、それらの製造および医薬としての使用
JP2011506361A (ja) * 2007-12-10 2011-03-03 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト 新規２−ヘタリールチアゾール−４−カルボキサミド誘導体、それらの製造および医薬としての使用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FRANCISCO-JAVIER GAMO, ET AL.: "Thousands of chemical starting points for antimalarial lead identification", NATURE, vol. 465, no. 7296, 20 May 2010 (2010-05-20), LONDON, UNITED KINGDOM, pages 305 - 310+2PP *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US12161625B2 (en) 2016-08-26 2024-12-10 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
JP2023537909A (ja) * 2020-08-21 2023-09-06 カナプ セラピューティクス インコーポレイテッド プロスタグランジンｅ２受容体に対して阻害活性を有する新規化合物及びその使用
JP7698708B2 (ja) 2020-08-21 2025-06-25 カナプ セラピューティクス インコーポレイテッド プロスタグランジンｅ２受容体に対して阻害活性を有する新規化合物及びその使用

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